ChapterPDF Available

Hodgkin's Lymphoma: From Tumor Microenvironment to Immunotherapeutic Approach - Body's Own Power Protection Challenges

Authors:
  • Hospital de Tortosa Verge de la Cinta, Tortosa, Spain
4
Hodgkin’s Lymphoma:
From Tumor Microenvironment to
Immunotherapeutic Approach – Body’s
Own Power Protection Challenges
Marylène Lejeune1, Luis de la Cruz-Merino2 and Tomás Álvaro3
1Molecular Biology and Research Section,
Hospital de Tortosa Verge de la Cinta, IISPV, URV,
2Clinical Oncology Department, Hospital Universitario Virgen Macarena, Sevilla,
Member of the Grupo Oncológico para el Tratamiento de las Enfermedades Linfoides
(GOTEL),
3Pathology Department, Hospital de Tortosa Verge de la Cinta, IISPV, URV,
Spain
1. Introduction
Hodgkin’s lymphoma (HL) is a highly curable disease and the reported results in last years
relative to patient’s survival were continuously improved. Cure rates > 90% for early HL
and > 70% for those with advanced HL are expected. Nevertheless, there are high-risk
patients (about 35%) refractory to initial treatment or relapse after achieving complete
remission. The current approaches to identify these patients employ pathologic, clinical and
classical biologic prognostic factors. The relative scarcity of markers that could reliably
predict long-term survival generates excessive treatments with both radio- and
chemotherapy for many patients. In this condition, the identification of innovative biologic
markers that could help to design appropriately tailored treatment strategies for classic HL
(cHL) patients at high risk of treatment failure and patients with low-risk disease remains a
crucial challenge.
The presence of a characteristic inflammatory microenvironment in response to tumoral
cells not only distinguishes HL from other lymphomas, but even more, this is the main
characteristic that makes HL a separate entity itself allowing its diagnosis. However, the
functional role of the microenvironment in the pathophysiology of HL remains a matter of
debate. The ability of the immune system to act as a double-edge weapon, protective or
stimulating, indicates that tumoral clearance requires the effective coordination of the
different elements of the immune system in an appropriate balance in quantity and quality.
Therefore, current cancer research in HL aims to develop methods to increase the
effectiveness of host antitumoral immune response, or at least prevent that various
cytokines and growth factors from different subpopulation of infiltrating reactive immune
response do not contribute to real growth of the tumoral Hodgkin and Reed-Sternberg
(H/RS) cells.
Hodgkin's Lymphoma
64
Biological therapy (also called immunotherapy, biotherapy or biological response modifier
therapy) is one of the most promising strategies. These therapies use the body’s immune
system, either directly or indirectly, to fight HL or to help lessen the side effects of some
cancer treatments for HL. Current biological therapy treatments for HL may be used either
alone or in conjunction with other modalities such surgery, radiation and chemotherapy.
This chapter summarizes the data on clinical, histological, pathological and biological
factors in HL, with special emphasis on the improvement of prognosis and their impact on
therapeutical strategies. The recent advances in our understanding of HL biology and
immunology seem indicate that infiltrated immune cells in the tumoral microenvironment
may play different, even opposite, functions according to the signals it senses. Strategies
aimed at interfering with the crosstalk between H/RS cells and their cellular partners have
been taken into account in the development of new immunotherapy’s that target different
cell components of HL microenvironment. The current standard approaches with the use of
combined modality therapy and systemic chemotherapy as well as the promising role of
future response-adapted strategies is reviewed.
2. Histopathological diagnostic parameters
As classified by the World Health Organization (WHO), HL exists in 5 types (Swerdlow et
al., 2008b). Four of these—nodular sclerosis (NSHL), mixed cellularity (MCHL), lymphocyte
depleted (LDHL), and lymphocyte rich (LRHL)—are referred to as cHL. The fifth type,
nodular lymphocyte predominant Hodgkin disease (NLPHL), accounts for 4–5% of all HL
cases and is a distinct entity with unique clinical features and a different treatment
paradigm. Regarding cHL, NSHL represents the most common histological type in
European countries, accounting for 40–70% of cases whereas MCHL account for about 30%.
Histologically, cHL is characterized by a minority of neoplastic cells (1-2%) named H/RS
cells embedded in a rich background composed of a variety of reactive, mixed inflammatory
cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes
(Figure 1A). Thus, the presence of an appropriate cellular background—along with the
results of immunophenotyping—is basic for the diagnosis. Evidence has accumulated that
H/RS cells harbor clonally rearranged and somatically mutated immunoglobulin genes,
indicating their derivation, in most cases, from germinal center (GC) B-cells (Kuppers, 2002;
Kuppers et al., 2003; Staudt, 2000; Thomas et al., 2004). Some HL cases have been identified
in which the H/RS is of T-cell origin but these are rare, accounting for 1-2% of cHL. Under
normal conditions, GC B-cells, that lack a functional high affinity antibody, undergo
apoptosis in the germinal center. H/RS cells show a characteristically defective B-cell
differentiation program, lose the capacity to express immunoglobulin and, therefore, should
die. However, H/RS cells escape apoptosis and instead proliferate, giving rise to the tumor
and the immune response that characterizes (Kuppers, 2002; Kuppers et al., 2003; Staudt,
2000; Thomas et al., 2004). Gray zones between cHL and some types of diffuse B-cell
lymphoma, especially primary mediastinal large B-cell lymphoma have been appreciated
during these last 20 years (Campo et al., 2011). Both share a close biologic relationship and
similar profiling at the epigenetic level (Eberle et al., 2011).
Concerning the phenotypic findings, expression of the CD30 molecule by H/RS cells is seen
in more than 98% of cHLs although the intensity of the immunostaining can vary from one
case to another, and even within the same case. CD30 molecule appears also to be a possible
target for specific antibodies conjugated with toxins and administered to patients with cHL
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
65
Fig. 1. Reed-Sternberg cell (A: black arrow) seen in a cellular background rich in
lymphocytes of a classical Hodgkin lymphoma. Popcorn cell (B: black arrow) with typically
lobated nuclei seen in a Nodular lymphocyte predominant Hodgkin lymphoma.
for therapeutic purposes. Preliminary studies have shown that these immunotoxins have
remarkable cytotoxic activity (Falini et al., 1992; Foyil & Bartlett, 2010; Tazzari et al., 1992).
CD15, characteristic but not specific for H/RS, is detected in about 80% of cHL patients
(Ascani et al., 1997; Foyil & Bartlett, 2010; Pileri et al., 1991; Pileri et al., 1995). H/RS cells
usually lack CD45 (Falini et al., 1990; Filippa et al., 1996; Korkolopoulou et al., 1994),
whereas B and, to lesser extent, T cell markers are seen in a proportion of cases. In
particular, CD20 is found in 30%–40% of cHL cases (usually EBV negative) (Filippa et al.,
1996), and CD79a is found even less often (Tzankov et al., 2003a; Tzankov et al., 2003c;
Watanabe et al., 2000). Positivity (usually weak) for one or more T cell marker is detected in
a minority of cases in H/RS cells (Casey et al., 1989; Falini et al., 1987). Under these
circumstances, single cell PCR studies have shown T-cell receptor (TCR) gene
rearrangement in only three instances, with clonal Ig gene rearrangements occurring in most
cHL cases with T-cell marker expression (Marafioti et al., 2000; Muschen et al., 2000). In
contrast to that seen in NLPHL, the elements of cHL show variable expression of the BCL6
molecule (Stein et al., 2008b). Antibodies against the nuclear-associated antigens Ki-67 and
proliferating cell nuclear antigen (PCNA) stain most H/RS cells, suggesting that a large
number of neoplastic cells enter the cell cycle (Gerdes et al., 1987; Sabattini et al., 1993).
NLPHL differs greatly from the common type in terms of morphology, phenotype,
genotype, and clinical behavior (Piccaluga et al., 2011). The only feature shared by NLPHL
and cHL is the low number of neoplastic cells. The neoplastic population consists of large
elements called lymphocytic/histiocytic or popcorn cells (Figure 1B) (Mason et al., 1994).
However, these neoplastic cells have a characteristic profile, which differs greatly from that
of cHL (Anagnostopoulos et al., 2000; Harris et al., 2000; Harris et al., 1994). In particular,
they are CD45+, CD20+, CD22+, CD79a+, J chain+/, EMA+/, and CD15. CD30 positivity is
rare and, when detected, weak. Popcorn cells regularly express the transcription factor
OCT2 and its coactivator BOB.1 (Stein et al., 2001). Although NLPHL is characterized by a
more preserved B-cell phenotype compared to the classical variant, a certain degree of
defectivity was also described since a downregulation of several markers associated with
the B-cell lineage (CD19, CD37, CD79b, and LYN) and with the germinal center maturation
stage (CD10, LCK, and PAG) have been observed (Tedoldi et al., 2007). In comparison to
A B
Hodgkin's Lymphoma
66
cHL, NLPHL has a higher age of onset (30-40 years), a higher incidence in males, a tendency
for peripheral distribution, lack of B symptoms in the majority of cases, and mostly early-
stage disease (Diehl et al., 1999; Nogova et al., 2008).
3. Clinicobiological prognostic parameters
The high curability rates of HL coupled with increasing awareness of late treatment related
morbidity, especially in young population, has highlighted the importance of some
clinicobiological risk factors that might guide the therapeutical strategies. Although these
factors are probably the clinical translation of some alterations at the molecular level, to
date there exist global consensus based upon these clinicobiological characteristics in order
to decide the total amount of treatment to administer to every single patient, especially with
respect to the type and number of cycles of chemotherapy, and thus to apply more intensive
treatments to those cases with higher risk of relapse and, on the contrary, to avoid
unnecessary treatment in patients with good prognosis.
3.1 Staging and clinical risk categories
Selection of treatments depends on initial risk stratification. In this sense, stage remains the
most important factor in the initial approach for treatment of HL, being the Ann Arbor
system with Cotswolds modifications the current staging system used for patients with HL
(Table 1) (Diehl et al., 2004).
Stage I — Involvement of a single lymph node region (I) or of a sin
g
le extral
y
mphatic or
g
an
or site (Ie).
Stage II — Involvement of two or more l
y
mph node re
g
ions on the same side of the
diaphra
g
m alone (II) or with involvement of limited, conti
g
uous extral
y
mphatic or
g
an or
tissue (IIe). The number of anatomic regions should be indicated by a subscript
Stage III — Involvement of l
y
mph node re
g
ions or l
y
mphoid structures on both sides of the
diaphra
g
m (III) which ma
y
include the spleen (IIIs) or limited, a conti
g
uous extral
y
mphatic
organ or site (IIIe) or both (IIIes). This may be subdivided into stage III-1 or III-2: stage III-1
is used for patients with involvement of the spleen or splenic hilar, celiac or portal nodes;
and stage III-2 is used for patients with involvement of the paraaortic, iliac, in
g
uinal, or
mesenteric nodes.
Stage IV — Diffuse or disseminated foci of involvement of one or more extral
mphatic
organs or tissues, with or without associated lymphatic involvement.
Table 1. Ann-Arbor/Costwolds staging system.
In clinical practice, HL is classified in early and advanced disease (Connors, 2005). Early
disease includes stages I-II and it is generally divided into favorable and unfavorable
categories based upon the presence or absence of certain clinical features, such as age,
erythrocyte sedimentation rate (ESR), B symptoms, and large mediastinal adenopathy.
Cooperative research groups have used diverse definitions of favorable and unfavorable
prognosis disease (Table 2) (Specht & Hasenclever, 1999).
However, probably the most commonly used definition of favorable/unfavorable disease is
the one proposed by the European Organization for the Research and Treatment of Cancer
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
67
(EORTC). Patients with one of the risk factors mentioned above are considered to have
unfavorable prognosis early stage HL. This stratification is highly pertinent and useful since
patients with favorable prognosis disease may have acceptable outcomes with less intensive
therapy than that required for those with unfavorable prognosis early stage or advanced
stage disease (Engert et al., 2010).
EORTC: a
g
e 50 or older; lar
g
e mediastinal adenopath
y
; with an ESR of more than 50/h and
B s
y
mptoms (or with an ESR of more than 30 mm/h in those who have B s
y
mptoms); and
disease with four or more regions of involvement
GHSG: Three or more sites
of disease; extranodal extension; mediastinal mass measurin
g
one-third the maximum thoracic diameter or
g
reater; and ESR more than 50 mm/h (more
than 30 mm/h if B symptoms present)
NCCN: lar
g
e mediastinal adenopath
y
; bulk
y
disease la
g
er than 10 cm; B s
y
mptoms; ESR
more than 50 mm/h; and disease with four or more regions of involvement
NCI-C: a
g
e 40 or older; ESR more than 50 mm/h; and disease with four or more re
g
ions of
involvement
Table 2. Definitions of unfavorable disease by different cooperative research groups.
Among patients with advanced stage HL (stage III/IV, and for some groups stage II plus
bulky nodal disease), prognosis is largely determined by the International Prognostic Score
(IPS) (Hasenclever & Diehl, 1998). The IPS was created by the IPS Project on Advanced
Hodgkin's Disease based upon the total number of seven potential unfavorable features at
diagnosis: serum albumin less than 4 g/dL, hemoglobin less than 10.5 g/dL, male gender,
age over 45 years, stage IV disease, white blood cell count 15,000/microL, and lymphocyte
count less than 600/microL and/or less than 8 percent of the white blood cell count.
In this system, one point is given for each of the above characteristics present in the patient,
for a total score ranging from zero to seven, representing increasing degrees of risk. When
applied to an initial group of 5141 patients with HL treated with combination chemotherapy
ABVD-like with or without radiotherapy, event-free survival rates at five years correlated
well with IPS (Table 3) (Hasenclever & Diehl, 1998).
No factors —84% (7 percent of patients)
One factor — 77% (22 percent of patients)
Two factors — 67% (29 percent of patients)
Three factors — 60% (23 percent of patients)
Four factors — 51% (12 percent of patients)
Five or more factors — 42% (7 percent of patients)
Table 3. Event free survival correlated with IPS.
Consequently, different treatment policies are indicated upon the presence of these
clinicobiological parameters, with application of more aggressive approaches when more
risk factors are present.
3.2 Positron Emission Tomography (PET) and correlation with clinical outcomes
In the last years, F fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has
been established as a potent tool that can provide early information about disease control in
Hodgkin's Lymphoma
68
the course of antineoplastic therapy. Monitoring clinical evolution with PET is emerging as a
new powerful predictor of outcome that can eventually diminish the amount of treatment to
administer, sparing unnecessary cycles of chemotherapy or radiotherapy, or, on the
contrary, making advisable the indication of more intensified treatments.
Some trials have revealed that interim PET scans after one to three cycles of chemotherapy
may predict long term outcomes in HL (Hutchings et al., 2005). In a prospective trial
including 260 patients with advanced HL treated with ABVD, PET scans were made per
protocol after 2 cycles of treatment (Gallamini A et al, 2007). This study demonstrated that
patients with an interim negative PET scan had excellent prognosis, with two year event free
survival rates of 95%, compared with 13% in those cases with PET positive. On multivariate
analysis, interim PET status was the only significant prognostic factor, showing superiority
over the classical IPS model (Gallamini et al., 2007).
After these findings, next question is how to incorporate the interim PET results in the
global management of treatment of HL in order to tailor a risk-adapted treatment strategy to
the individual patient. There are several prospective trials ongoing in the United States and
in Europe in early and advanced disease, testing different therapeutic approaches
depending on PET scan findings. Their results are eagerly awaited to definitely establish
finer tune therapeutic strategies in this disease.
4. Role of virus in HL
A negative association has been observed between HL and repeated early common
infections (Rudant et al., 2010). Viruses are etiologically associated with a significant number
of human leukaemia/lymphomas. Recognition of virus involvement in these malignancies
is important as prevention of infection can lead to a reduction in the number of individuals
at risk of disease. Early epidemiologic data suggested that HL develops among persons with
a delayed exposure to a ubiquitous infectious agent such as Epstein-Barr virus (EBV) or
among persons with acquired less common new infections such as human deficiency virus
(HIV). The role of mediators of immunity genes may be important in the lack of adequate
immune control of infectious agents. Several cytokines and interleukins are produced by
neoplastic cells in lymphomas.
EBV, a herpesvirus with a worldwide distribution, is present in H/RS cells of 40%–60% of
cHL lesions and contributes to their pathogenesis (Kapatai & Murray, 2007; Khan, 2006).
EBV positivity is higher with MCHL (60-70%) than with NSHL (15-30%). EBV+ H/RS cells
express the latent membrane proteins 1, 2A y 2B (LMP1, LMP2A, LMP2B), the EBV nuclear
antigens 1 (EBNA1), and the EBER RNAs, but consistently lack EBNA2 (latency II) (Jarrett,
2002, 2006). LMP1 is likely to contribute to survival and proliferation of H/RS cells through
activation of NF-κB and AP-1 (Kilger et al., 1998; Lam & Sugden, 2003). The role of LMP2A
is more difficult to predict. Although LMP2A can deliver a survival signal in B-cells, H/RS
cells have down-regulated many B-cell specific molecules including intracellular
components involved in this signaling pathway (Kilger et al., 1998; Schwering et al., 2003).
LMP2A may indeed contribute to this ‘loss of B-cell signature’, since cDNA microarray
analysis of LMP2A expressing B-cells reveals a similar pattern of downregulated genes
(Portis et al., 2003). It is also possible that EBNA1 and the EBERs contribute to the rescue of
H/RS cells from apoptosis (Kennedy et al., 2003; Young & Rickinson, 2004).
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
69
Immunologic reactions (cytotoxic responses) against EBV can occur in the peripheral blood of
some cHL patients (Khan, 2006). It has been estimated that EBV-specific T-cells might
constitute up to 5% of circulating CD8+ T-cells (Hislop et al., 2002; Rickinson & Kieff, 2001).
The intratumoral immunological alterations induced by EBV+ H/RS cells remain unclear. The
abnormal network of cytokines/chemokines and/or their receptors in H/RS cells is involved
in the attraction of many of the microenvironmental cells into the lymphoma background.
There is increasing evidence suggesting a change in the balance between Th1 and Th2 cells in
the pathogenesis of HL and that this change induces reactivation of latent viral infections,
including EBV. For example, interleukin like IL-1 is produced by H/RS cells in culture (Hsu
et al., 1989) and IL-3 have demonstrated to present significant biological activity as growth and
antiapoptotic factor for H/RS cells (Aldinucci et al., 2005). Serum levels of the receptor
antagonist IL-1 (IL-1r ) are elevated in HL patients, patients with B symptoms have
significantly lower levels of IL-1r than those without symptoms (Gruss et al., 1992). IL-10 is a
pleiotropic cytokine that protects hematopoietic cells from apoptosis induced by
glucocorticoids and doxorubicin. H/RS cells express functional IL-10 receptors and elevated
IL-10 levels may inhibit apoptosis of H/RS cells. Elevated serum IL-10 levels have been found
in up to 50% of HL patients and have been associated with inferior failure free survival (FFS)
and overall survival (OS) in patients treated with ABVD or BEACOPP chemotherapy (Rautert
et al., 2008; Sarris et al., 1999; Vassilakopoulos et al., 2001; Viviani et al., 2000). Elevated serum
IL-10 levels confer a poor survival and may add to the prognostic value of the IPS in prediction
of outcomes in HL (Axdorph et al., 2000). CCL17/TARC is a chemokine secreted by H/RS
cells and its chemotactic properties may explain the infiltration of reactive T lymphocytes in
HL (Niens et al., 2008; Peh et al., 2001; van den Berg et al., 1999). Elevated CCL7/TARC levels
have been seen in the majority of patients with HL (Niens et al., 2008). Persistent elevation of
TARC after completion of treatment has been associated with poorer survival and could be
important for treatment monitoring (Hnatkova et al., 2009; Weihrauch et al., 2005). EBV-
infected H/RS cells were shown to stimulate also the stromal production of particular
chemokines such as the interferon-inducible chemokine IP-10 (CXCL10) (Teichmann et al.,
2005), Rantes/CCL5 (Aldinucci et al., 2008; Fischer et al., 2003), the ligand CCL28 (Hanamoto
et al., 2004), CCL20 that is capable of attracting regulatory T cells (Baumforth et al., 2008) and
the macrophage-derived chemoattractant (MDC)/CCL22 (Niens et al., 2008). It has been also
suggested that immunologic reactions against EBV can occur in the peripheral blood of some
cHL patients (Khan, 2006). However, no comprehensive characterization of intratumoral
immunologic alterations induced by EBV+ H/RS cells has been described so far. EBV was
shown to contribute to HL patients survival (Kapatai & Murray, 2007). The observation of
Th1/antiviral response in EBV+ cHL tissues provides a basis for novel treatment strategies
(Chetaille et al., 2009; Skinnider & Mak, 2002).
Although HL is not considered an acquired immunodeficiency syndrome (AIDS)-defining
neoplasm, HIV-infected patients treated with highly active antiretroviral therapy (HAART)
present a higher incidence of HL compared with the population without HIV infection
(Powles & Bower, 2000; Powles et al., 2009). Almost 100% of HIV-associated cases are EBV-
positive and, in these patients, EBV is found more frequently in H/RS cells (Powles &
Bower, 2000). HIV-HL exhibits pathological features that are different from those of HL in
‘‘general population’’(Carbone et al., 2009; Grogg et al., 2007) while is characterized by the
predominance of unfavorable histological subtypes (MCHL and LDHL) (Carbone et al.,
2009; Grogg et al., 2007; Tirelli et al., 1995). One of the peculiar clinical features of HIV-cHL
Hodgkin's Lymphoma
70
is the widespread extent of the disease at presentation and the frequency of systemic B-
symptoms. At the time of diagnosis, 70–96% of the patients have B-symptoms, and 74–92%
have advanced stages of disease with frequent involvement of extranodal sites, the most
common being bone marrow (40–50%), liver (15–40%), and spleen (around 20%) (Tirelli et
al., 1995). The widespread use of HAART has resulted in substantial improvement in the
survival of patients with HIV infection and lymphomas because of the reduction of the
incidence of opportunistic infections and the opportunity to allow more aggressive
chemotherapy. Moreover, the less-aggressive presentation of lymphoma in patients treated
with HAART compared with untreated patients may also favorably change the outcome for
HIV-infected patients with lymphomas (Vaccher et al., 2003). In fact, compared with
patients who never received HAART, patients in HAART before the onset of cHL generally
are older, have less B-symptoms, and a higher leukocyte and neutrophil counts and
hemoglobin level (Chimienti et al., 2008).
5. Antitumoral immunity
Tumors are more than an accumulation of neoplastic cells; they might be more properly
considered as a functional tissue immunologically mediated and formed by a complex tissue
network in which neoangiogenesis, infiltrating immune competent cells, stromal cells, and a
differentiated and specific extracellular matrix constitute the tumor microenvironment with
the capacity of regulating cancer development (Alvaro et al., 2010; Tlsty & Coussens, 2006).
The interplay between the host immune system, malignant cells, and all other components
of tumoral stroma determine proliferation, invasion, angiogenesis, and remodelling of
extracellular matrix and metastasis.
The hypothesis of immunesurveillance postulates that one of the principal functions of the
immune system would be recognizing neoplastic cells and eliminating them before they
form tumors (Burns & Leventhal, 2000). In these conditions, the absence of an effective
immune system increases the risk of developing cancer. If the immune system is a complex
system of different types of cells and molecules whose primary function is to act as an
effective tumor suppressor, it is certain that the system may behave inefficiently, as
indicated by the fact of tumors in immunocompetent individuals. Thus, in addition to the
concept of immunosurveillance arises of immunostimulation (Ichim, 2005). Although
various mechanisms could induce immunosuppression (virus, transplant ..), the increasing
likelihood of cancer (Burnet, 1957) in immunologically intact individuals suggests that the
immune response might not only be ineffective but may itself contribute to tumor
progression (Prehn, 1972). That is, the immune system has the ability to act as a double-
edged sword, indicating that tumor elimination requires a good coordination of the various
elements of the immune system.
The products of mutated or deregulated genes of tumoral cells contribute to the growth and
invasion of tumoral cells, as well as to the expression of proteins with the ability to stimulate
the immune response. The immunogenic capacity of the tumor can be evaluated by means
of the study of the reactive infiltration, which is mainly composed by innate immune cells.
The nature, function and specificity of the effector cells that drive the antitumoral immune
response have been widely studied. Innate immunity is represented essentially by dendritic
cells (DCs), macrophages, natural killer (NK), NK/T cells, neutrophils, cytokines and
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
71
complement proteins, whereas adaptive immune cells are represented by B lymphocytes,
CD4+ T-helper lymphocytes and CD8+ cytotoxic lymphocytes (CTL). The general
mechanisms for tumor suppression have been principally attributed to CD4+ T helper
lymphocytes. Cytokines and lymphokines from CD4+ T cells can also activate CD8+ CTL,
NK cells and macrophages, which have all been shown to be involved in tumor immunity
(Adam et al., 2003; Gonthier et al., 2004; Ikeda et al., 2002; Peipp & Valerius, 2002; Smyth et
al., 2002). Immunoregulatory cytokines such as IL-10 and TGF- play an important role in
immune tolerance, and it seems that suppressor effect of regulatory T cells (CD4+CD25+) on
the development of tumor associated antigen-reactive lymphocytes is independent of
cytokines (Aldinucci et al., 2005). Contributing to the complexity of the interactions between
the reactive background and malignant cells, immune cells present in the local infiltrate
have proved capable of modulating apoptosis and of inducing proliferation of tumoral cells
via death receptors, cytotoxic granule liberation, and withdrawal of growth factors or
production of immunosuppressive cytokines (Atkinson & Bleackley, 1995; Berke, 1995; de
Visser & Kast, 1999; Skinnider & Mak, 2002). The efficacy of tumoral–immune cells
interactions depends on several factors, such as the expression of MHC class I molecules
and immunogenic epitopes in tumoral cells, the type of immune cell and the accessibility of
tumor cells.
Tumor antigens recognized by T cells (generally CD8+ lymphocytes) represent the principal
target of antitumoral immunity and are presented by MHC class I molecules; that is to say,
that tumoral cells behave as antigen presenting cells (APC), presenting their own antigens to
T cells. Naturally, professional APC can also present antigens to CD4+ lymphocytes through
MHC class II molecules (Quezada et al., 2010). Dendritic cells (DC) and other APC are
dispersed between tissues as sentinels or alarm systems ready to detect the presence of
foreign antigens. While in the tumor microenvironment IL-12 production tends to be
suppressed, resulting in a decrease in Th1 activity, DCs represent probably the most
important regulators of naïve T cells, with a great capacity to produce and release IL-12. In
their process of polarization, DCs are under the influence of inflammatory mediators such
as prostaglandins produced by macrophages, fibroblasts, and tumor cells. A new route of
junction between innate and adaptive immunity through the interaction between DC and
NK cells has been suggested (Adam et al., 2005). Actually, at least four distinct CD4 T cells
subsets have been described: Th1, Th2, Th17, and regulatory T cells, each one with a unique
cytokine secretion pattern and function (Zhu & Paul, 2008). Their primary roles is providing
cytokines for the development of CTL, in addition to being able to secrete tumor necrosis
factor (TNF) and interferon (IFN)-gamma, which can increase the expression of MHC class I
by the tumor cell and therefore increase its sensitivity to CTL lysis. Among natural CTL,
natural killer cells (NK cells) can be activated directly by contact with the tumor or as a
result of the stimulus provided by cytokines. In addition, lymphokine-activated killer cells
(LAK) are a group of NK cells derived from peripheral blood cells or tumor infiltrating
lymphocytes (TIL) in patients with high concentrations of IL-2 and show a high capacity,
nonspecific in this case, to lyse tumor cells. Others cellular mediators such as the
macrophages are also capable of lysing tumor cells by releasing a large amount of lysosomal
enzymes and reactive oxygen metabolites. Once activated they also produce cytokines such
as TNF that exerts its cytotoxic activity triggering apoptosis in a similar way to that
mediated by Fas.
Hodgkin's Lymphoma
72
6. Molecular markers
In HL, a striking feature of both NLPHL and cHL entities is that the malignant cells account
for only around 1% of the tumor mass (Stein et al., 2008a). However, notable significant
differences exist between these entities in terms of natural history, relation to EBV, cell
morphology, phenotype, molecular characteristics, and clinical behavior (Farrell & Jarrett,
2011; Maggioncalda et al., 2011).
There is compelling evidence that H/RS cells are clonal B cells that have lost their B cell
phenotype. Effectively, H/RS cells, from nearly all cHL cases, and malignant popcorn cells
from NLPHL have detectable rearrangements of Ig heavy andor light chain genes,
confirming a B cell origin (Kuppers et al., 1996; Kuppers et al., 1994) and, in any given case,
the rearrangements are identical, proving the clonal nature of the disease (Kanzler et al.,
1996; Kuppers et al., 1994; Marafioti et al., 2000). Furthermore, the Ig variable (IgV) gene
regions show evidence of somatic hypermutation, revealing a GC or post-GC origin
(Kuppers, 2002). It was also suggested that cHL and B cell non-Hodgkin lymphoma (BNHL)
arisen from a common precursor (pre-GC or GC B cell) since both generally harbor identical
IgV gene rearrangements but have distinct somatic Ig gene mutations (Brauninger et al.,
2006). Intraclonal IgV gene diversity is observed in popcorn cells, indicating ongoing
somatic hypermutation, whereas identical somatic hypermutations were observed in H/RS
cells indicating a later stage of B cell differentiation (Kanzler et al., 1996; Kuppers et al., 1994;
Marafioti et al., 2000). Around 25% of cHL cases present non-functional Ig genes due to
“crippling” mutations (Brauninger et al., 2006; Kanzler et al., 1996; Kuppers et al., 1994;
Kuppers et al., 2001). H/RS cells harbor uncommonly rearranged T cell receptor genes
(<2%), suggesting a T cell origin in a small minority of cases (Muschen et al., 2001; Muschen
et al., 2000; Seitz et al., 2000). At phenotypic level, markers of B lineage (CD20, CD19, CD79,
surface Ig) and transcription factors (OCT2, BOB1 and PU1) are generally down-regulated in
H/RS cells (Hertel et al., 2002; Schwering et al., 2003), and expression of the B cell-specific
transcription factor PAX5 is usually retained (Foss et al., 1999). In contrast, popcorn cells
express B cell markers including CD20, CD79, PAX5, OCT2 and BOB1. The global
suppression of the B cell signature results from transcriptional reprogramming (Kuppers et
al., 2003; Mathas et al., 2006; Nie et al., 2003; Renne et al., 2006; Smith et al., 2005; Ushmorov
et al., 2006; Ushmorov et al., 2004).
Mature B cells lacking B cell receptors would normally die by apoptosis, and therefore
H/RS cells must have developed mechanisms to facilitate survival. The escape from
apoptosis and transcriptional reprogramming of H/RS cells are interlinked and seem
important to disease pathogenesis. EBV gene products appear to contribute to H/RS cell
survival, proliferation and reprogramming through dysregulation of several signaling
networks and transcription factors such as intrinsic overexpression of CD30 (Horie et al.,
2002), deleterious mutations of the genes encoding IB proteins (IB(Emmerich et al.,
1999; Emmerich et al., 2003; Jungnickel et al., 2000; Lake et al., 2009; Wood et al., 1998) and
amplification of the chromosomal region including the c-Rel gene (Barth et al., 2003; Joos et
al., 2002; Martin-Subero et al., 2002). In cHL EBV-associated cases, the virus can contribute
directly to activation of NF-B though its protein latent membrane protein 1 (LMP-1), which
mimics CD40 signaling. Mutations of genes encoding inhibitors and regulators of NF-B
such as inactivating mutations of the TNF- induced protein 3 (TNFAIP3) gene have been
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
73
detected in a large proportion of EBV-negative cases (Kato et al., 2009; Schmitz et al., 2009).
Others genomic lesions affecting different signaling pathways in H/RS cells (JAK-STAT,
PI3K–Akt–mTOR, MAPK–MEK–ERK and AP1–JunFos) have also been demonstrated
(Dutton et al., 2005; Emmerich et al., 1999; Joos et al., 2003; Juszczynski et al., 2007; Kube et
al., 2001; Skinnider et al., 2002; Weniger et al., 2006; Zheng et al., 2003). In cHL and primary
mediastinal B-cell lymphoma, genomic breaks of the major major histocompatibility
complex (MHC) class II transactivator CIITA have been demonstrated to be highly recurrent
(15% and 38% respectively) (Steidl et al., 2011b). The functional consequences of CIITA gen
fusions is the downregulation of surface HLA class II expression and overexpression of
ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and
CD273/PDL2). These receptor-ligand interactions have been shown to impact anti-tumour
immune responses in several cancers, whereas decreased MHC class II expression has been
linked to reduced tumour cell immunogenicity.
Several of these recurring genetic lesions appear correlated with disease outcome (Slovak et
al., 2011). Nonrandom DNA copy number alterations in cHL (H/RS cells CD30+) have been
identified in the molecular karyotypes of cHL as comparing with the genomic profiles of GC
B cells. Frequent gains (>65%) were associated with growth and proliferation, NF-κB
activation, cell-cycle control, apoptosis, and immune and lymphoid development. Frequent
losses (>40%) observed encompassed tumor suppressor genes, transcriptional repressors
and SKP2 (Slovak et al., 2011).
Thus, multiple transcriptional and signaling pathways are disrupted in HL, and are thought
to cooperate to increase H/RS cell proliferation, reduce apoptosis and promote a favorable
cellular microenvironment through the release of multiple cytokines and chemokines. These
findings may be useful prognostic markers in the counselling and management of patients
and for the development of novel therapeutic approaches in primary refractory HL.
7. Biological factors: Immune response in HL
The tumor microenvironment consists of a specific mixture of immune cells that express a
distinctive profile for each tumor type, from which the efficacy of the immune response
against the tumor is eventually derived (Alvaro et al., 2009). Exist increasing evidence of the
importance of the microenvironment in the molecular pathogenesis of HL (Steidl et al.,
2011a), and a promising therapeutic target has been raised focused on this approach. The
presence of a characteristically rich inflammatory background particularly distinguishes HL
from other lymphoproliferative syndromes. Differences in gene expression profiles of
malignant cells in lymphoproliferative syndromes do not always determine the
aggressiveness of the lymphoma, while recent contributions determine that HL represents
the prototypical tumor in which the interplay between H/RS and the reactive
microenvironment determines not only the histological morphology and classification but
also the clinicopathological features and prognosis of these patients. Quantitative analysis of
infiltrating immune cells reveals undisclosed relationships between the relative proportion
of these cells and HL clinical outcome, illustrating how factors other than tumoral
cellularity, or the immunophenotype and molecular anomalies present in the H/RS cells,
can play a role in tumoral behaviour.
Hodgkin's Lymphoma
74
7.1 Patterns of immune response in HL and prognosis
An abnormal pattern with overexpression of cytokines and their receptors is characteristic in
H/RS cells. This pattern explains the abundant mixture of inflammatory cells, stromal
changes and the predominance of Th2 cells between the various subpopulations of
lymphoid cells in the tumoral microenvironment of HL (Swerdlow et al., 2008b). A
predominance of CD4+ T lymphocytes in the background of tumoral cells in addition to a
high number of cytotoxic cells (CD8, CD57, TIA-1) has been observed in the majority of HL-
tissues (Figure 2) (Alvaro-Naranjo et al., 2005; Oudejans et al., 1997; Poppema et al., 1998).
Fig. 2. Immunohistochemical staining of inflammatory background in HL: T lymphocytes
(CD4 and CD8), NK cells (CD56 and CD57) and cytotoxic cells (GrB and TIA-1).
Regardless of the classic clinical and pathological features, a high proportion of infiltrating
CD8+ and CD57+ cells as well as a low number of infiltrating CTL (evaluated by the presence
of Granzyme B and TIA-1) appear to be associated with a favorable outcome for HL patients
(without B symptoms and lower clinical stages) and better response to treatment (Alvaro-
Naranjo et al., 2005; Alvaro et al., 2005; Ansell et al., 2001). It is unclear to date whether the
presence of CD8+ T cells correlates with the antitumor cytotoxic response. Nevertheless, it
has been suspected that CD8+ T cells may be recruited in an antigen-non-specific mode in
HL (Willenbrock et al., 2000).
Although the activation status of infiltrating cells have been demonstrated to be
independent of the degree of malignancy in HL (Bosshart, 2002), others studies have shown
that the presence of activated cytotoxic T cells (granzyme B+) is associated with unfavorable
follow-up in these patients (Kanavaros et al., 1999; Oudejans et al., 1997; ten Berge et al.,
2001). A higher level of not activated cytotoxic cells (TIA-1+) has been observed in advanced-
stage cHL without prognostic value (Camilleri-Broet et al., 2004). However, TIA-1+ CTL
associated with the presence of regulatory T cells FOXP3+ appears to play an important role
in monitoring HL patients (Alvaro et al., 2005). Variations in the level ofcytotoxic TIA-1+ and
regulatory T cells observed during the course of the disease could be implicated in the
progression of HL (Alvaro et al., 2005).
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
75
CD21
+
/S100
+
DC
CD57
+
/CD56
+
NK cells
CD4
+
T cells CD8
+
T cells GrB
+
activated
CTL
CD68+
TAM FOXP3
+
T cells
TIA-1
+
resting
CTL
EBV+ B symptoms
NS subtype
NS subtypes
Leucocytosis
B symptoms
Stage III/IV
NS subtype
Leucocytosis
No CR treatment
No CR treatment
EBV+
B symptoms
Stage III/IV
HL REACTIVE MICROENVIRONMENT
PATTERN OF IMMUNE ESCAPE
AGGRESSIVE BEHAVIOR
B
CD21
+
/S100
+
DC
CD57
+
/CD56
+
NK cells
CD4
+
T cells CD8
+
T cells GrB
+
activated
CTL
CD68+
TAM FOXP3
+
T cells
TIA-1
+
resting
CTL
EBV- No B symptoms
MC subtyp e
MC subtypes
No leucocytosis
No B symptoms
Stage I/II
MC subtype
No leucocytosis
CR treatment
CR treatment
EBV-
No B symptoms
Stage I/II
HL REACTIVE MICROENVIRONMENT
PATTERN OF IMMUNOSURVEILLANCE
INDOLENT BEHAVIOR
A
CD21
+
/S100
+
DC
CD57
+
/CD56
+
NK cells
CD4
+
T cells CD8
+
T cells GrB
+
activated
CTL
CD68+
TAM FOXP3
+
T cells
TIA-1
+
resting
CTL
EBV+ B symptoms
NS subtype
NS subtypes
Leucocytosis
B symptoms
Stage III/IV
NS subtype
Leucocytosis
No CR treatment
No CR treatment
EBV+
B symptoms
Stage III/IV
HL REACTIVE MICROENVIRONMENT
PATTERN OF IMMUNE ESCAPE
AGGRESSIVE BEHAVIOR
B
CD21
+
/S100
+
DC
CD57
+
/CD56
+
NK cells
CD4
+
T cells CD8
+
T cells GrB
+
activated
CTL
CD68+
TAM FOXP3
+
T cells
TIA-1
+
resting
CTL
EBV- No B symptoms
MC subtyp e
MC subtypes
No leucocytosis
No B symptoms
Stage I/II
MC subtype
No leucocytosis
CR treatment
CR treatment
EBV-
No B symptoms
Stage I/II
HL REACTIVE MICROENVIRONMENT
PATTERN OF IMMUNOSURVEILLANCE
INDOLENT BEHAVIOR
A
Fig. 3. Representation of the two immune patterns observed in HL significantly associated
with their clinicopathological features. The immunesurveillance pattern (A) with a high
proportion of infiltrating T lymphocytes, NK cells, DCs, activated CTL but low proportion
of resting CTL and TAM is associated with a favorable outcome. The immune escape
pattern (B) with a high proportion of infiltrating resting CTL and TAM, but low proportion
of T lymphocytes, NK cells, DCs and activated CTL is associated with an unfavorable
outcome. MC, mixed celularity; NS, nodular sclerosis; CR, complete response.
Association of tumor-associated macrophages (TAM) CD68+ with adverse clinical outcomes
has been confirmed in several studies in hematologic and solid tumors (Pages et al., 2010).
Hodgkin's Lymphoma
76
Recently, a gene expression profile analysis performed on 130 biopsy samples from patients
with HL identified a signature of TAM and monocytes that was predictive of treatment
failure (Steidl et al., 2010). In this study the sensitivity and specificity of this GEP signature
for outcome in this cohort was greater than that of the International Prognostic Score (IPS).
After these findings, biopsy samples from an independent cohort of 166 patients were
evaluated with immunohistochemistry for the presence of CD68 expressing macrophages
using a score from 1 to 3, from lower to higher infiltration (Steidl et al., 2010). When
compared with those with low CD68 expression, patients with tumors that demonstrated an
increased number of CD68 expressing macrophages had shorter median progression-free
survival (PFS), lower rate of 10-year disease-specific survival (60 versus 89%), and higher
failure rate of secondary treatment with curative intent (63 versus 13%). It has been also
recently demonstrated that high level of CD68 correlated with poorer survival, event-free
survival (EFS) and with the presence of EBV in the tumor cell population (Kamper et al.,
2011). These results suggest a new pathological prognostic factor to be considered, however
it is unclear at this time how CD68 status should affect patient management.
A plausible explanation for the extensive inflammatory infiltrate present in HL secretion could
be a variety of cytokines produced by both tumor cells and surrounding stromal tissue. CD4+
T cells produce Th2 cytokines that could contribute to local suppression of the cellular immune
response mediated by Th1. However, the categorization of CD4+ T cells in Th1 and/or Th2 is
an oversimplification (Marshall et al., 2004) as regulatory T cells with CD4+CD25+ phenotype
not only play a regulatory role of autoimmunity, but also have suppressive effects on the
development of antigen-reactive lymphocytes associated with the tumor (Wei et al., 2004). The
H/RS cells secrete high amounts of chemokine, thymus and activation-regulated chemokine
(TARC) and macrophages-derived chemokine (MDC) in particular, which attract lymphocytes
expressing CCR4 receptor, such as Th2 (Skinnider & Mak, 2002). These cytokines may
contribute to the pathogenesis of the disease initiated and sustained the presence of the
reactive infiltrate. Alternatively, immune cells can produce cytokines responsible for
proliferation and survival of tumor, producing a positive feedback between the tumoral cells
and immune system. The composition of the infiltrate may also differ depending on the state
of immunosuppression of HL patients. Moreover, HIV infection affects, for direct or indirect
mechanisms, both reactive changes as neoplastic lymphoid tissue. Recently we have seen a
significant loss of intratumoral T cells CD4+ (CD4/CD8 ratio reversal) and a decrease in
intratumoral activated CTL in patients with HIV-infected HL (Bosch Princep et al., 2005). A
low proportion of CD4+ cells appears also to be significantly related to EBV status, probably
due to the relation with the local tumor-associated suppression of EBV-specific T-cell
responses observed in EBV+ HL cases (Frisan et al., 1995).
7.2 Immune response regulation in HL
Tumors employ a plethora of immunosuppressive mechanisms, which may act in concert to
counteract effective immune responses. Different mechanisms have been suggested to
account for the CTL-mediated apoptosis resistance of H/RS cells, such as the
downregulation of MHC class I molecules of the H/RS cells, prevention of recognition of
tumor-associated antigens by CTLs (Poppema & Visser, 1994), or the local secretion of both
IL-10 and transforming growth factor-b by H/RS cells (Newcom et al., 1988; Ohshima et al.,
1995), which are able to inhibit CTL function. In this respect, it appears that the blockage of
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
77
the Granzyme B pathway of apoptosis through the overexpression of serine protease
inhibitor PI-9/SPI-6 is an important additional mechanism for immune escape by tumors
(Medema et al., 2001). The expression of PI9 tends to be associated with a high percentage of
activated CTLs, especially in HL (Bladergroen et al., 2002), suggesting that PI9 may play a
role in protecting against Granzyme B-induced apoptosis, and partially explaining why
tumors expressing high levels of PI9 have a particularly poor clinical outcome, irrespective
of the number of Granzyme B+ cells in the inflammatory infiltrate.
Different subsets of immune cells contribute also to this immunosuppressive network,
including CD4+CD25+ regulatory T cells. In HL, it has been initially proposed that CD4+ T
cells produce cytokines of Th2 type that could contribute to local suppression of the cellular
immune response mediated by Th1 cells (Bladergroen et al., 2002; Poppema et al., 1999).
However, the categorization of CD4+ T cells in Th1 and/or Th2 constitutes an
oversimplification and it has been shown that regulatory T cells with CD4+CD25+ phenotype
not only play a role in controlling autoimmunity, but also have suppressive effects on
lymphocyte development tumor associated antigen reagents (Curiel et al., 2004; Fontenot et
al., 2003; Suri-Payer et al., 1998). Functional and molecular characterization of these cells has
been facilitated by the identification of markers such as FOXP3 and others (Shimizu et al.,
2002; Sutmuller et al., 2001; Takahashi et al., 2000). FOXP3 encodes a transcription factor
known as Scurfina, specifically expressed by T cells CD4+CD25+(Karube et al., 2004), that
acts converting naïve regulatory T cells CD4+CD25- phenotype to CD25+ (Hori et al., 2003).
More recently, it was suggested that regulatory T cells and PD1+ T cells interact with H/RS
cells (Alvaro et al., 2005; Teichmann et al., 2005; Yamamoto et al., 2008), which produce the T
regulatory attractant galectin-1 and the PD-1 ligand, PDL-1 (Yamamoto et al., 2008). On the
other hand, the observation of numerous CXCR3+ lymphocytes in some HL tumors has
raised the possibility of an occasional Th1-predominant immune response (Alvaro-Naranjo
et al., 2005).
The regulatory T cells can inhibit the production of both IL-2 to regulate the high expression
of IL-2Rα (CD25), ie, delay or block the activation of CD8+ cells and natural killer (NK) cells
against tumor antigens (Azuma et al., 2003; Wolf et al., 2003). The immunosuppressive
properties of regulatory T cells appear to be particularly important because of its large effect
on cellular cytotoxicity represented by CTLs and NK cells. The presence of low numbers of
FOXP3+ cells and a consequent high rate of TIA-1
+ cells in the infiltrate represents an
independent prognostic factor negatively affecting the survival of the disease. Furthermore,
when the disease relapses and progresses, larger number of TIA-1+ cells and lower
proportion of FOXP3+ on the reactive background of the tumor are also prone to be seen
(Alvaro et al., 2005).
8. Apoptotic and cell cycle pathways in HL
The aberrant expression of proteins involved in regulation and execution of apoptosis and
cell cycle of lymphocytes has been demonstrated in several types of lymphoma and the
importance of the level of apoptosis and proliferation in clinically aggressive
lymphoproliferative syndromes (Bai et al., 2005; Bai et al., 2003; Garcia et al., 2003; Sanchez-
Beato et al., 2003). These anomalies are probably not sufficient to explain the development of
lymphomas, even if the effectiveness of therapy is presumed to be mediated by activation of
apoptosis (Messineo et al., 1998). In HL, different studies have described alterations in genes
Hodgkin's Lymphoma
78
controlling apoptosis and proliferation of H/RS cells and biological factors such as EBV
detection, which influence the clinical aggressiveness of the disease (Bargou et al., 1997;
Garcia et al., 1999; Hinz et al., 2002; Hinz et al., 2001; Izban et al., 2001; Kupper et al., 2001;
Leoncini et al., 1997; Mathas et al., 2002; Montesinos-Rongen et al., 1999; Morente et al., 1997;
Sanchez-Beato et al., 1996). These studies have demonstrated alterations of the p53, Rb and
p27 tumor suppressor pathways (Bai et al., 2005; Garcia et al., 1999; Guenova et al., 1999;
Hinz et al., 2001; Lauritzen et al., 1999; Montesinos-Rongen et al., 1999; Morente et al., 1997;
Sanchez-Beato et al., 1996; Sanchez-Beato et al., 2003; Tzardi et al., 1996), overexpression of
cyclins involved in the G1/S and G2/M transition such as cyclins E, D2, D3, A and B1
(Garcia et al., 2003; Kolar et al., 2000; Leoncini et al., 1997; Ohshima et al., 1999; Teramoto et
al., 1999; Tzankov et al., 2003b), overexpression of cyclin-dependent kinases such as CDK1, 2
and 6 (Garcia et al., 2003) and overexpression of the anti-apoptotic proteins c-FLIP, bcl-xl, c-
IAP2 and surviving (Brink et al., 1998; Garcia et al., 2003; Kanavaros et al., 2000; Kuppers,
2002; Kuppers et al., 2003; Staudt, 2000; Thomas et al., 2004).
These findings raised the questions of how H/RS cells escape apoptosis, acquire self-
sufficiency in growth signals and proliferate (Kuppers, 2002; Kuppers et al., 2003; Staudt, 2000;
Thomas et al., 2004). The physiologic relevance of the deregulation of the cell cycle and
apoptosis regulators in cHL could be related to the different probabilities of survival of HL
patients. Many studies have analyzed the clinical relevance of the expression of cell cycle and
apoptosis regulators in cHL using IHC or gene expression profiling (Brink et al., 1998;
Devilard et al., 2002; Garcia et al., 2003; Montalban et al., 2000; Morente et al., 1997; Smolewski
et al., 2000). Shorter survival was significantly associated with high proliferation index (Ki67),
high expression of bcl2, bcl-xl, bax and p53, low expression of Rb and caspase 3 and high
apoptotic index (Montalban et al., 2004; Rassidakis et al., 2002a; Rassidakis et al., 2002b; Sup et
al., 2005; Abele et al., 1997; Brink et al., 1998; Garcia et al., 2003; Montalban et al., 2004; Morente
et al., 1997; Smolewski et al., 2000). Evidence has accumulated that the constitutive activation
of the NF-B pathway in H/RS cells is of particular importance for explaining the apoptosis
deregulation in cHL by up-regulating an anti-apoptotic gene expression program (Bai et al.,
2005; Hinz et al., 2002; Hinz et al., 2001; Mathas et al., 2002). By gene expression profiling, the
good outcome cHL were characterized by up-regulation of genes involved in apoptosis
induction (APAF, bax, bid, caspase 8, p53, TRAIL) and cell signaling, including cytokines and
transduction molecules (IL-10, IL-18, STAT3), while the bad outcome cHL were characterized
by upregulation of genes involved in cell proliferation (Ki67) and by down-regulation of
tumor suppressor genes PTEN (Phospatase and Tensin homolog deleted on chromosome 10)
and DCC (Deleted in Colorectal Cancer) (Devilard et al., 2002).
Within the complexity of the interactions between the reactive substance and tumor cells,
immune cells present in the infiltrate have been shown to modulate the apoptosis and
proliferation of tumor cells via apoptotic receptors, cytotoxic granule release, growth factors
or immunosuppressive cytokines (Atkinson & Bleackley, 1995; Berke, 1995; de Visser &
Kast, 1999; Famularo et al., 1994; Hahne et al., 1996). IHC study has demonstrated that the
antiapoptotic profile observed in H/RS cells is associated with a general increase in CD4+ T
cells infiltrating (related to Bcl-XL and Mcl-1) and an overall decline CD8+ T lymphocytes
infiltrating, NK cells and dendritic cells (related to Bcl-XL and Bax) (Alvaro et al., 2008).
Alterations observed in the G1-S checkpoint of H/RS cell cycle, in the principal tumor
suppressor pathways Rb-p16INK4a and p27KIP1, and the high rate of proliferation (MIB1,
BCL6) are also strongly associated with higher infiltration of the overall immune response
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
79
against the tumor (Alvaro et al., 2008). These results point to the regulation of proteins
involved in apoptosis and proliferation of tumor cells by direct interactions between these
cells and the surrounding inflammatory microenvironment.
These infiltrated cells are able to activate apoptotic caspase proteolytic cascade through TNF
receptor superfamily interactions (FasL/Fas and CD40/CD40L). The different members of
this superfamily share common cell signaling pathways that mediate the activation of
nuclear factor NF-κB and mitogen-activated protein kinases. In this case, CD40/CD40L
interactions are known to induce the upregulation of Bcl-XL and Mcl1 expression and to
mediate the activation of NF-B (Hinz et al., 2001; Hong et al., 2000; Inoue et al., 2000; Kater
et al., 2004; Lee et al., 1999; Metkar et al., 2001). CTLs are also able to trigger a second
proapoptotic pathway through the protease granzyme B, which, once released from CTLs, is
translocated into the target cell by perforin, where it activates the effector caspase cascade
(Thome & Tschopp, 2001). On the other hand, the wide variety of cytokines and chemokines
present in HL tumoral tissue (IL-2, IL-4, IL-6, and IL-13), responsible for the massive influx
of activated immune cells (Poppema et al., 1999), has been shown to regulate the expression
of the various members of Bcl2 family, such as the antiapoptotic Bcl2 homologues Bcl-XL
and Mcl1 and the proapoptotic Bax (Akbar et al., 1996; Jourdan et al., 2000; Puthier et al.,
1999; Song et al., 2002; Tang et al., 2002).
Likewise for the apoptotic markers, the physiologic signals present in the reactive
microenvironment also interfere with components of the G1-CDK checkpoint (cyclin D3,
CDK6, and p27) (Malumbres & Barbacid, 2001; Wagner et al., 1998). The constitutively
activated NF-B has also been shown to induce changes in the expression of a set of proteins
regulating cell cycle progression and gene transcription, including cyclin D1, p53, p16
INK4a, and p27KIP1 (Hinz et al., 2001; Sanchez-Beato et al., 2003). Cytotoxic cells are able to
induce directly the permanent down-regulation of p27KIP1, probably as a consequence of
increased degradation mediated by SKP2, a ubiquitin ligase for p27KIP1 (Blanchard et al.,
1997; Ren et al., 2005; Wagner et al., 1998). Related with the heightened proliferative state in
these tumors is the high level of expression of Bcl6, a multifunctional regulator that is able
not only to down-regulate cyclin D2 and p27KIP1 expression (Shaffer et al., 2000) but also to
repress Bcl-XL (Tang et al., 2002).
The presence of EBV was significantly associated with the overexpression of STAT1 and
STAT3. STAT3 was found to be associated with a low infiltration of CD4 T lymphocytes and
a high infiltration of activated cytotoxic cells. Although STAT1 is considered to be a
potential tumor suppressor (promoting apoptosis), STAT3 is thought to be an oncogene
because it leads to the activation of cyclin D1 and Bcl-XL expression and is involved in
promoting cell cycle progression and cellular transformation and in preventing apoptosis
(Calo et al., 2003).
The physiologic relevance of these relationships could be related to the different
probabilities of survival of HL patients. Different sets of deregulated immune and tumoral
genes have shown to be associated with a therapeutically unfavorable response in HL
patients (Sanchez-Aguilera et al., 2006). For example, altered expression of bcl-2 and the bcl-
2 family of proteins (e.g., bcl-Xl, BAX) in H/RS cells may prevent apoptosis and explain
resistance to treatment-induced apoptosis. Under these conditions, the concomitant analysis
of the immune infiltrate and the apoptotic/proliferative pathways of tumoral cells should
provide more accurate information about the specific molecular pathways critical for cancer
Hodgkin's Lymphoma
80
cell growth. Possible molecules that interfere with these molecular links, particularly some
enzymes representative of the immune metabolic state or tumoral cell cycle (Sanchez-
Aguilera et al., 2006), might be pharmaceutically manipulated and could be candidates for
new therapeutic targets pertinent to patient care.
9. HL in immunosuppressed patients
Epidemiologic and molecular findings suggest that cHL is not a single disease but consists
of more than one entity and may occur in different clinical settings. According to the
acknowledged international literature (Swerdlow et al., 2008a), cHL arises either in the
general population (Stein et al., 2008a) but also in the immunosuppressed host, specifically
in HIV-infected individuals (Raphael et al., 2008), and in post-transplant patients, most often
in renal post-transplant patients (Swerdlow et al., 2008c).
From a clinical perspective, HIV-infected HLs have some peculiarities. Firstly, it must be
distinguished two eras, before and after the widespread use of highly active antiretroviral
therapy (HAART) (Powles et al., 2009). Before HAART, HIV-HL patients were generally
diagnosed with an aggressive presentation. Advanced stages were the rule at diagnosis with
frequent involvement of extranodal sites, particularly bone marrow, liver and spleen. In
addition, up to 95% of patients had systemic B symptoms when diagnosed, and
consequently survival rates were extremely disappointing (Tirelli et al., 1995). Nevertheless,
introduction of HAART have led to forms of presentation less aggressive, a dramatic
reduction in the incidence of opportunistic infections, and finally it have allowed to
complete curative treatment with chemotherapy in most of the patients (Carbone et al.,
2009). Regarding chemotherapy, optimal treatment for HIV-HL has not been definitely
established due to the relatively low incidence of this disease. However, little phase II
studies with few patients have found that, in this modern HAART era, standard ABVD
treatment may be safely administered with or without growth-colony stimulating factors
(G-CSF) support (Xicoy et al., 2007), although some groups argue in favor of G-CSF
introduction from the beginning to minimize risks. Prophylaxis against Pneumocystis
jiroveci infection with trimethoprim-sulfamethoxazole is also strongly recommended in all
these patients. Other more intensive regimens like BEACOPP or Stanford V with
consolidation radiotherapy have been tested with acceptable results in terms of complete
responses (100% and 81%, respectively), although a higher incidence of opportunistic
infections and hematologic toxicity were registered. Finally, even the use of high dose
chemotherapy and autologous stem cell transplantation have been demonstrated feasible in
HL-HIV relapsed patients with curative purposes (Carbone et al., 2009). To conclude, it
must be said that clinical outcomes of patients with HIV-HL has improved after HAART
introduction, with higher curability rates when a combined antineoplastic and antiretroviral
strategy is followed and completed.
Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of
monoclonal or polyclonal lymphoproliferative lesions that occur in immunosuppressed
recipients after solid-organ or bone marrow transplantation. cHL occurs in the post-
transplant setting, most often in renal transplant patients, is almost always EBV-positive and
should complete the diagnostic criteria for cHL (Adams et al., 2009; Knight et al., 2009;
Rohr et al., 2008; Swerdlow et al., 2008c). All patients received post-transplant
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
81
immunosuppression and/or antiviral agents (Dharnidharka et al., 2004; Goyal et al., 1996;
Krishnamurthy et al., 2010). Clinically, the majority of patients are men and all ages are
affected. Generally, the time from transplant to the onset of the disease ranges from few
months (4–6 months) to several years, with a median time of 113 months. Half cases
presented as extranodal masses, especially in the liver or in the lung even if other extranodal
sites (especially tonsil) can be involved. The best therapeutic approach is not well defined
yet. Recently, rituximab has gained favor in the treatment of PTLD because of its targeting
of CD20-positive B cells, with fairly promising results (Pham et al., 2002).
The iatrogenic lymphoproliferative disorders are lymphoid proliferations or lymphomas
that arise in patients treated with immunosuppressive drugs. Among iatrogenic
lymphoproliferative disorders, other than PTLD, there is an increase in frequency of cHL
and lymphoid proliferations with Hodgkin-like features. Thus, lesions containing RS-like
cells but do not fulfill the criteria of CHL, the so-called Hodgkin-like lesions, have been
included in this setting (Gaulard et al., 2008). Because CHL has only recently been
recognized as an iatrogenic complication, few cases have been reported in the medical
literature (Gaulard et al., 2008).
10. Antineoplastic therapy in HL: From classical to biological therapies
Chemotherapy and radiotherapy remain the cornerstone of HL treatment. Especially,
polychemotherapy schedules have increased the survival rates in these patients along the
last decades. Nevertheless, up to 30% and 10% of patients will recur and die of HL in
advanced and early disease respectively, and unlike what happened in non Hodgkin
lymphomas, newer active compounds against HL have not been introduced in clinic since
the early 1970s. In addition, patients exposed to chemotherapy and radiation fields are at
highest risk of lethal second malignancies (Friedberg, 2011). Therefore it would be more
than desirable having new therapeutic drugs and strategies for a better control of the disease
and minimizing toxicity of therapy, especially when relapses occur.
10.1 Conventional treatment
Nowadays HL is considered one of the most oncological curable diseases, as a matter of fact
of its extremely chemo and radiosensitivity. Among chemotherapy options, ABVD
(doxorubicin, bleomycin, vinblastine and dacarbazine) represent the standard schedule for
HL treatment in the majority of centers worldwide. However the management of advanced-
stage cHL is often predicated on the IPS, and thus escalated BEACOPP (bleomycin,
etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) is
another schedule to consider, especially in high-risk patients with IPS scores of 4 or greater
(Diehl et al., 2003). Therefore, an apparently more effective initial treatment may be
unattractive because of increased toxic effects (Connors, 2011) and highest risk of second
malignancies, especially in relation with large radiation fields (Ng et al., 2002).
Canellos et al showed in 1992 that ABVD was equally effective and less toxic than MOPP
(mechlorethamine, vincristine, procarbazine, prednisone) or MOPP alternating with ABVD,
and this has subsequently become the chemotherapy of choice worldwide (Canellos et al.,
1992). Although standard ABVD can cure most of HL, advanced stage- high risk patients
based on IPS still represent a major concern with EFS rates of 50% or less (Hasenclever &
Hodgkin's Lymphoma
82
Diehl, 1998). The HD9 trial conducted by Diehl et al showed that among patients with
advanced-stage cHL, ABVD is insufficient for patients with an IPS of 4 or more (Diehl A et
at, 2003). In this trial of the German Hodgkin Study Group (GHSG), 1,195 patients with
advanced-stage HL were recruited and randomized between COPP-ABVD, standard
BEACOPP, and escalated BEACOPP. For patients with an IPS of 4 or greater, the more
intensive regimen improved the freedom from treatment failure from 59% to 82% and OS
from 67% to 82%. It is important to underscore that there was no significant difference for
the more favorable groups. A 10-year update of this study confirms superiority of escalated
BEACOPP over COPP-ABVD for the high-risk patients (Diehl et al., 2003). However, there is
increased late toxicity with escalated BEACOPP, with more risk of sterility, infections and
secondary leukaemia’s, and thus universal application of this schedule for advanced-stage
disease remain difficult to implement.
In addition of chemotherapy, radiotherapy is another treatment modality frequently used in
HL. It is generally indicated in early disease, regardless of the favorable/unfavorable
stratification, and when bulky disease is present, or there remain residual foci of disease
after chemotherapy in advanced HL.
10.2 Impact of chemotherapy and radiotherapy on tumoral microenvironment
In the last few years, many interesting data have emerged about the enormous impact of the
antineoplastic treatments into the immune microenvironment of the tumors, which
demonstrate a sort of cancer vaccination effect (Haynes et al., 2008). In this sense,
chemotherapeutics like anthracyclines (included in all of the upfront standard treatments of
HL) and radiotherapy seem to induce a type of apoptotic death via calreticulin exposure and
release of the pro-inflammatory factor High Mobility Group Box-1 (HMGB1) with well
known immune stimulating properties (Tesniere et al., 2008).
Anthracyclines can induce a highly potent immune response by increasing antigen
(neoantigens) threshold and presentation (via antigen presenting cells), with enhancement
of T-cell response and generation of memory T cells (Obeid et al., 2007a). Other
chemotherapeutics like cyclophosphamide, etoposide and taxanes have also proved to have
an immunogenic effect in preclinical models (Tsavaris et al., 2002), however evidence is
scarce and further investigation is required.
These new concepts might serve to consider chemotherapeutics like anthracyclines as less
empirical and more specific drugs, and thus it would be desirable to customize
chemotherapies taking into account their potential effects on microenvironment. In this
sense, there is an interesting field of clinical research to discover that may combine classical
CT agents with immunogenic effects with boosting costimulators molecules like cytokines
(GM-CSF, IL2) (de la Cruz-Merino et al., 2008). Specifically in the case of the anthracycline´s
effect on cancer cells, the calreticulin exposure do not induce DC maturation which is, on the
contrary, one of the main effects of cytokines like GM-CSF that induce selective DC
maturation and activation, giving a strong rationale to combine these two therapeutic
modalities (anthracyclines and GM-CSF). These combinatorial strategies may eventually
sustain immunogenic effect of tumoral cell death. Regarding to this, biomarkers of immune
activity should be of the greatest interest, in order to serve as proof of principle of efficacy
with an earlier detection of the eventual benefits of oncological treatments in patients.
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
83
Furthermore, monitoring changes detected during oncological treatments in blood samples,
especially in immunophenotype, regulatory T cells amount and TCD8/regulatory T cells
ratio, may represent interesting biomarkers to analyze and validate in the future.
As happen with chemotherapy, the intrinsic radiosensitivity of malignant lymphocytes is
extremely high. Although the underlying mechanisms which explain it are not fully
elucidated, recently new evidence is emerging about some changes induced by radiation at
a molecular level, which may provoke a type of cell death highly immunogenic (Formenti &
Demaria, 2009). Ionising radiation has different immune effects regarding the dose
administered, and while in the case of low doses the final effect is mostly protumorigenic, at
higher doses with cytotoxic activity, cell death may induce tumoral neoantigens which can
be embraced by DC, and thus activate an effective adaptive immune response (Apetoh et al.,
2007). As with anthracyclines, the two critical mediators of this process seem to be
translocation of calreticulin to the cell surface and release of HMGB1 by the dying cells
(Formenti & Demaria, 2009). Both of them trigger danger signals which activate immune
mechanisms. In addition, surviving cancer cells after radiation show increased expression of
death receptors, adhesion molecules (ICAM-1) and major histocompatibility complex class I
(MHC-I), which activate APCs (Obeid et al., 2007b).
To conclude, some groups argue that these immune effects are the major determinants of the
therapeutical success of the antineoplastic treatments in oncological diseases, including HL.
10.3 Modern therapeutic approaches targeting the tumor microenvironment
Apart from chemotherapy and radiotherapy, other biological compounds with significant
effects upon tumor microenvironment like unconjugated and conjugated monoclonal
antibodies, radioimmunconjugates, immunotoxins and novel immunomodulatory
compounds like lenalidomide are under clinical investigation, and at this moment they
represent the most promising therapeutical strategies in HL. Recently, Kasamon et al
revised this topic (Kasamon & Ambinder, 2008) and pointed out three major HL therapeutic
targets: EBV, CD20 and CD30.
As previously cited, up to 40-60% of cHL might be associated with EBV and thus some EBV
antigens expressed on HL cells like latent membrane protein 1 and 2 (LMP1 and LMP2)
have been postulated as eventual immunotherapeutic targets. Some interesting results have
been obtained with the use of adoptive cellular immunotherapy with EBV-specific CTL
among patients with EBV-associated posttransplant lymphoproliferative diseases (Haque T
et al., 2007), rendering a proof of principle of activity for this approach. In a small study of
16 patients with relapsed or high risk EBV+ lymphoproliferative diseases that included cases
of HL, infusions of autologous LMP2- specific CTL induced clinical responses with tumor
regression in 5 of 6 patients with previously detectable tumor (Lucas et al., 2004).
After elucidation of the B cell origin of H/RS in classical HL, targeting B cell antigens on HL
has gained renewed interest. Specifically in classical HL, the monoclonal antibody anti-
CD20 Rituximab has shown activity as single agent or combined with chemotherapies like
ABVD and gemcitabine in different clinical settings (Kasamon & Ambinder, 2008). Impact of
rituximab on tumor microenviroment by depleting benign CD20+ cells, is postulated as the
main antineoplastic mechanism of action of this drug in HL, independently of CD20
expresssion on the H/RS cells. Rituximab has also been tested in the uncommon nodular
Hodgkin's Lymphoma
84
lymphocyte predominant Hodgkin lymphoma, with impressive clinical results (Rehwald et
al., 2003; Ekstrand et al., 2003) that merit further investigation.
Among new molecular targets in HL, the member of the tumor necrosis factor (TNF)-
receptor family CD30 merits special consideration. CD30 is expressed abundantly on RS
cells of HL, and in other numerous lymphoid malignancies of B-, T-, and natural killer (NK)-
cell origin (Deutsch et al., 2011). Regarding its biological activity CD30 has pleiotropic
biologic functions, being capable of promoting cell proliferation and survival as well as
inducing antiproliferative responses and cell death. Final effects of CD30 activation seem
largely dependent on the microenvironment context (Deutsch et al., 2011). Unconjugated
anti-CD30 antibodies have been tested in phase I and II studies showing limited clinical
activity (Kasamon & Ambinder, 2008). On the contrary, another attractive approach as it is
the use of antibody–drug conjugates (ADCs) have rendered better results.
Brentuximab vedotin (SGN-35) is an ADC consisting of chimeric anti-CD30 antibody cAC10
(SGN-30) conjugated to the tubulin destabilizer monomethylauristatin E (MMAE) (Okeley et
al., 2010). In an initial phase I dose escalation study, brentuximab vedotin was administered
at a dose of 0.1–3.6 mg/kg every 3 weeks to 45 patients with relapsed or refractory CD30-
positive lymphomas, primarily HL and ALCL (Younes et al., 2010). Brentuximab vedotin
was well tolerated and associated mainly with grade 1 or 2 adverse events including
neutropenia and peripheral neuropathy. Objective response was observed in 17 (38%)
patients, including 11 (24%) complete remissions, with a median duration of response of 9.7
months. Tumor regression was observed in 86% of patients. The maximum tolerated dose
was 1.8 mg/kg, and of 12 patients who received this dose, six patients (50%) had an
objective response (Younes A et al, 2010). A second phase I study, with weekly brentuximab
vedotin resulted in an objective response rate of 59% and rapid median time to response.
Anti-tumor activity was similar to that observed for dosing once every 3 weeks. However,
significant peripheral neuropathy was observed with continued weekly dosing, so the
administration every 3 weeks was preferred for phase II studies (Deutsch et al., 2011).
Clearly, brentuximab vedotin is an exciting new agent in the setting of relapsed HL and
other lymphoid neoplasms CD30+. Multiple clinical trials are ongoing including different
clinical settings and combinations with chemotherapy, in order to find the safer and more
successful way of administering this drug.
11. Body’s own power protection challenges in HL
Evidences in the literature suggest that targeting elements of the tumor microenvironment,
or signaling pathways in tumor cells activated as a consequence of stromal interactions, may
prove a useful therapeutic strategy to prevent tumor development and progression.
However, given the tumor cells’ ability to circumvent various therapeutic agents when
given as monotherapy, the success of these agents is likely to be seen when used in
combination with existing treatments.
Apart from the infiltrating immune competent cells, the complex tissue network of the
tumor microenvironment is also formed by neoangiogenesis, stromal cells, and a
differentiated and specific extracellular matrix. Among stromal cells, there are
macrophages—derived from hematopoietic stem cells, fibroblasts, adipocytes, and
osteoblasts. In order to delay or circumvent tumor progression, a number of strategies are
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
85
being developed to disrupt tumor-stroma interactions (Hiscox et al., 2011). Macrophages
and fibroblasts within the tumor microenvironment present an important point for
therapeutic intervention by using agents which reverse their phenotype or block key growth
factor receptors (Allavena et al., 2005; Banciu et al., 2008; Hagemann et al., 2008; Hiscox et
al., 2011; Karin & Greten, 2005). On the other hand, the regulation of adhesion between
cancer cells and the surrounding matrix by different kind of integrins activates tumor cell
signaling pathways that result in growth progression, invasion and migration (Green et al.,
2009; Hiscox et al., 2011; Inoki et al., 2002; Kim et al., 2009; Parsons et al., 2008; Stupp &
Ruegg, 2007).
The different immunotherapeutic models that have been tested for the treatment of HL
include unconjugated monoclonal antibodies (Ansell et al., 2007; Bartlett et al., 2008; Klimm
et al., 2005), immunotoxins (Falini et al., 1992; Kreitman et al., 2000),
radioimmunoconjugates (Klimm et al., 2005; Schnell et al., 2005) and, most recently,
immunomodulatory compounds (Bollard et al., 2004; Borchmann et al., 2002; Davies et al.,
2001; Hartmann et al., 2001; Hartmann et al., 1997; Maier & Hammond, 2006; Roskrow et al.,
1998). Some strategies, in particular radioimmunotherapeutic approaches and
immunotoxins have already shown significant effectivity (Friedberg, 2011). First experiences
with relatively non-toxic immunomodulatory compounds have implemented a whole new
kind of immunotherapy in NLPHL where the anti-CD20-antibody Rituximab might be the
future effective but less toxic treatment (Ekstrand et al., 2003; Schulz et al., 2008).
The integration of the new biologic markers evaluated in HL, that clearly driving force for
an abnormal local and systemic antitumor immunity in HL, make of HL an ideal candidate
for immunotherapeutic strategies (Rathore & Kadin, 2010; Younes, 2009). The pro-survival
and pro-death receptors expressed by tumoral cells are currently being explored for novel
treatment strategies by using a variety of naked and conjugated monoclonal antibodies.
Furthermore, signaling pathways triggered by these receptors and other intracellular
proteins can now be therapeutically inhibited by a variety of small molecules. Nowadays,
the present challenge remains to know the best way to implement immunotherapeutic
concepts into the current treatment concepts of HL in order to conserve or even improve the
good long term survival in these patients and to reduce toxicity and long-term side-effects.
12. Conclusion
Although the relatively good prognosis and high current overall cure rate of cHL, it is
important to underscore that clinicobiological factors still remain the main information to
guide treatment policies in HL. Due to the fact that this disease is commonly diagnosed in
young population, and antineoplastic treatments may induce worrying iatrogenic
consequences in terms of secondary tumors (solid and hematologic malignancies),
cardiopathies or respiratory long-term morbidities among others, it is indispensable to
administer always the minimum effective and curative therapy. In this sense, beyond the
well known clinical risk factors, interim information in the course of chemotherapy of PET
scans will probably aid in the next future to apply a less empiric and more tailored and
personalized treatment. Since early 90´s ABVD schedule represent the standard treatment of
HL for curative purposes worldwide and little has changed in clinical practice in the last
two decades. However there is room for improvement since a significant percentage of
patients will ultimately relapse after successful treatment.
Hodgkin's Lymphoma
86
The recent research activities led to a better understanding of the phenotype, molecular
characteristics, histogenesis, and possible mechanisms of HL lymphomagenesis. There is
complete consensus on the B-cell derivation of the tumor in most cases, and on the relevance
of EBV infection and defective cytokinesis in at least a proportion of patients. The influence
of the cellular components of the microenvironment and that of the elaborate network of
interactions they produce, on the clinical course of HL, has progressively emerged over the
past decades. The expression of a variety of cytokines and chemokines by the tumoral cells
is believed to drive an abnormal immune response and additional factors secreted by
reactive cells in the microenvironment help to maintain the inflammatory milieu. In these
conditions, tumoral cells manipulate microenvironment, permitting them to develop their
malignant phenotype fully and evade host immune response attack. The interplay between
tumoral cells and the reactive microenvironment determines not only the histological
morphology and classification but also the clinicopathological features and prognosis of
these patients. Genes and proteins expression signatures derived from immune cells have
demonstrated to correlate well with response to treatments the outcome of HL patients
respectively. This could be critical to the development of adoptive T-cell therapies that
target the virus or different cell components of HL microenvironment. In aggressive HL, the
development of prognostic systems modelled on the integration of biologic prognostic
markers appears essential for more appropriate risk stratification.
New knowledge about impact of chemotherapy upon microenvironment has changed old
paradigms, conferring to some cytotoxic agents like anthracyclines immunogenic properties
that can explain the final mechanism of action of these drugs. These discoveries are
extremely important since give a strong rationale to exploit this activity in the context of
combinatorial strategies that might include other immunogenic agents like cytokines and
monoclonal antibodies, among others. Therefore, it is conceivable to hypothesize that
chemotherapy can still improve its efficacy in HL in the next future. Furthermore, recently
new molecules have shown impressive clinical activity in HL. It is the case of the antibody-
drug conjugate anti-CD30 brentuximab vedotin that have obtained very promising results in
relapsed CD30+ lymphomas, and thus has given place to ongoing phase III confirmatory
studies.
To summarize, the incorporation of PET scans in HL diagnostic and follow-up algorithms,
the widespread use of the new prognostic molecular and biological factors at diagnosis, the
new highly effective molecules and the recent knowledge regarding chemotherapy effects
on microenviroment, permit forsee a different and customized therapeutical approach to HL
in the next future.
13. References
Abele, M.C.; Valente, G.; Kerim, S.; Navone, R.; Onesti, P.; Chiusa, L.; Resegotti, L. &
Palestro, G. (1997). Significance of cell proliferation index in assessing histological
prognostic categories in Hodgkin's disease. An immunohistochemical study with
Ki67 and MIB-1 monoclonal antibodies. Haematologica, Vol.82, No.3, pp. 281-285,
0390-6078
Adam, C.; King, S.; Allgeier, T.; Braumuller, H.; Luking, C.; Mysliwietz, J.; Kriegeskorte, A.;
Busch, D.H.; Rocken, M. & Mocikat, R. (2005). DC-NK cell cross talk as a novel
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
87
CD4+ T-cell-independent pathway for antitumor CTL induction. Blood, Vol.106,
No.1, pp. 338-344, 0006-4971
Adam, J.K.; Odhav, B. & Bhoola, K.D. (2003). Immune responses in cancer. Pharmacol Ther,
Vol.99, No.1, pp. 113-132, 0163-7258
Adams, H.; Campidelli, C.; Dirnhofer, S.; Pileri, S.A. & Tzankov, A. (2009). Clinical,
phenotypic and genetic similarities and disparities between post-transplant and
classical Hodgkin lymphomas with respect to therapeutic targets. Expert Opin Ther
Targets, Vol.13, No.10, pp. 1137-1145, 1744-7631
Akbar, A.N.; Borthwick, N.J.; Wickremasinghe, R.G.; Panayoitidis, P.; Pilling, D.; Bofill, M.;
Krajewski, S.; Reed, J.C. & Salmon, M. (1996). Interleukin-2 receptor common
gamma-chain signaling cytokines regulate activated T cell apoptosis in response to
growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but
not pro-apoptotic (bax, bcl-xS) gene expression. Eur J Immunol, Vol.26, No.2, pp.
294-299, 0014-2980
Aldinucci, D.; Lorenzon, D.; Cattaruzza, L.; Pinto, A.; Gloghini, A.; Carbone, A. &
Colombatti, A. (2008). Expression of CCR5 receptors on Reed-Sternberg cells and
Hodgkin lymphoma cell lines: involvement of CCL5/Rantes in tumor cell growth
and microenvironmental interactions. Int J Cancer, Vol.122, No.4, pp. 769-776, 1097-
0215
Aldinucci, D.; Olivo, K.; Lorenzon, D.; Poletto, D.; Gloghini, A.; Carbone, A. & Pinto, A.
(2005). The role of interleukin-3 in classical Hodgkin's disease. Leuk Lymphoma,
Vol.46, No.3, pp. 303-311, 1042-8194
Allavena, P.; Signorelli, M.; Chieppa, M.; Erba, E.; Bianchi, G.; Marchesi, F.; Olimpio, C.O.;
Bonardi, C.; Garbi, A.; Lissoni, A.; de Braud, F.; Jimeno, J. & D'Incalci, M. (2005).
Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin):
inhibition of macrophage differentiation and cytokine production. Cancer Res,
Vol.65, No.7, pp. 2964-2971, 0008-5472
Alvaro-Naranjo, T.; Lejeune, M.; Salvado-Usach, M.T.; Bosch-Princep, R.; Reverter-Branchat,
G.; Jaen-Martinez, J. & Pons-Ferre, L.E. (2005). Tumor-infiltrating cells as a
prognostic factor in Hodgkin's lymphoma: a quantitative tissue microarray study
in a large retrospective cohort of 267 patients. Leuk Lymphoma, Vol.46, No.11, pp.
1581-1591, 1042-8194
Alvaro, T.; de la Cruz-Merino, L.; Henao-Carrasco, F.; Villar Rodriguez, J.L.; Vicente Baz, D.;
Codes Manuel de Villena, M. & Provencio, M. (2010). Tumor microenvironment
and immune effects of antineoplastic therapy in lymphoproliferative syndromes. J
Biomed Biotechnol, Vol.2010, pp. , 1110-7251
Alvaro, T.; Lejeune, M.; Escriva, P.; Pons, L.E.; Bosch, R.; Jaen, J.; Lopez, C.; Salvado, M.T. &
de Sanjose, S. (2009). Appraisal of immune response in lymphoproliferative
syndromes: a systematic review. Crit Rev Oncol Hematol, Vol.70, No.2, pp. 103-113,
1879-0461
Alvaro, T.; Lejeune, M.; Garcia, J.F.; Salvado, M.T.; Lopez, C.; Bosch, R.; Jaen, J.; Escriva, P. &
Pons, L.E. (2008). Tumor-infiltrated immune response correlates with alterations in
the apoptotic and cell cycle pathways in Hodgkin and Reed-Sternberg cells. Clin
Cancer Res, Vol.14, No.3, pp. 685-691, 1078-0432
Alvaro, T.; Lejeune, M.; Salvado, M.T.; Bosch, R.; Garcia, J.F.; Jaen, J.; Banham, A.H.;
Roncador, G.; Montalban, C. & Piris, M.A. (2005). Outcome in Hodgkin's
Hodgkin's Lymphoma
88
lymphoma can be predicted from the presence of accompanying cytotoxic and
regulatory T cells. Clin Cancer Res, Vol.11, No.4, pp. 1467-1473, 1078-0432
Anagnostopoulos, I.; Hansmann, M.L.; Franssila, K.; Harris, M.; Harris, N.L.; Jaffe, E.S.; Han,
J.; van Krieken, J.M.; Poppema, S.; Marafioti, T.; Franklin, J.; Sextro, M.; Diehl, V. &
Stein, H. (2000). European Task Force on Lymphoma project on lymphocyte
predominance Hodgkin disease: histologic and immunohistologic analysis of
submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern
and abundant lymphocytes. Blood, Vol.96, No.5, pp. 1889-1899, 0006-4971
Ansell, S.M.; Horwitz, S.M.; Engert, A.; Khan, K.D.; Lin, T.; Strair, R.; Keler, T.; Graziano, R.;
Blanset, D.; Yellin, M.; Fischkoff, S.; Assad, A. & Borchmann, P. (2007). Phase I/II
study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin's lymphoma
and anaplastic large-cell lymphoma. J Clin Oncol, Vol.25, No.19, pp. 2764-2769,
1527-7755
Ansell, S.M.; Stenson, M.; Habermann, T.M.; Jelinek, D.F. & Witzig, T.E. (2001). Cd4+ T-cell
immune response to large B-cell non-Hodgkin's lymphoma predicts patient
outcome. J Clin Oncol, Vol.19, No.3, pp. 720-726, 0732-183X
Apetoh, L.; Ghiringhelli, F.; Tesniere, A.; Obeid, M.; Ortiz, C.; Criollo, A.; Mignot, G.; Maiuri,
M.C.; Ullrich, E.; Saulnier, P.; Yang, H.; Amigorena, S.; Ryffel, B.; Barrat, F.J.; Saftig,
P.; Levi, F.; Lidereau, R.; Nogues, C.; Mira, J.P.; Chompret, A.; Joulin, V.; Clavel-
Chapelon, F.; Bourhis, J.; Andre, F.; Delaloge, S.; Tursz, T.; Kroemer, G. & Zitvogel,
L. (2007). Toll-like receptor 4-dependent contribution of the immune system to
anticancer chemotherapy and radiotherapy. Nat Med, Vol.13, No.9, pp. 1050-1059,
1078-8956
Ascani, S.; Zinzani, P.L.; Gherlinzoni, F.; Sabattini, E.; Briskomatis, A.; de Vivo, A.; Piccioli,
M.; Fraternali Orcioni, G.; Pieri, F.; Goldoni, A.; Piccaluga, P.P.; Zallocco, D.;
Burnelli, R.; Leoncini, L.; Falini, B.; Tura, S. & Pileri, S.A. (1997). Peripheral T-cell
lymphomas. Clinico-pathologic study of 168 cases diagnosed according to the
R.E.A.L. Classification. Ann Oncol, Vol.8, No.6, pp. 583-592, 0923-7534
Atkinson, E.A. & Bleackley, R.C. (1995). Mechanisms of lysis by cytotoxic T cells. Crit Rev
Immunol, Vol.15, No.3-4, pp. 359-384, 1040-8401
Axdorph, U.; Sjoberg, J.; Grimfors, G.; Landgren, O.; Porwit-MacDonald, A. & Bjorkholm,
M. (2000). Biological markers may add to prediction of outcome achieved by the
International Prognostic Score in Hodgkin's disease. Ann Oncol, Vol.11, No.11, pp.
1405-1411, 0923-7534
Azuma, T.; Takahashi, T.; Kunisato, A.; Kitamura, T. & Hirai, H. (2003). Human CD4+
CD25+ regulatory T cells suppress NKT cell functions. Cancer Res, Vol.63, No.15,
pp. 4516-4520, 0008-5472
Bai, M.; Papoudou-Bai, A.; Kitsoulis, P.; Horianopoulos, N.; Kamina, S.; Agnantis, N.J. &
Kanavaros, P. (2005). Cell cycle and apoptosis deregulation in classical Hodgkin
lymphomas. In Vivo, Vol.19, No.2, pp. 439-453, 0258-851X
Bai, M.; Tsanou, E.; Agnantis, N.J.; Chaidos, A.; Dimou, D.; Skyrlas, A.; Dimou, S.; Vlychou,
M.; Galani, V. & Kanavaros, P. (2003). Expression of cyclin D3 and cyclin E and
identification of distinct clusters of proliferation and apoptosis in diffuse large B-
cell lymphomas. Histol Histopathol, Vol.18, No.2, pp. 449-457, 0213-3911
Banciu, M.; Metselaar, J.M.; Schiffelers, R.M. & Storm, G. (2008). Antitumor activity of
liposomal prednisolone phosphate depends on the presence of functional tumor-
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
89
associated macrophages in tumor tissue. Neoplasia, Vol.10, No.2, pp. 108-117, 1476-
5586
Bargou, R.C.; Emmerich, F.; Krappmann, D.; Bommert, K.; Mapara, M.Y.; Arnold, W.; Royer,
H.D.; Grinstein, E.; Greiner, A.; Scheidereit, C. & Dorken, B. (1997). Constitutive
nuclear factor-kappaB-RelA activation is required for proliferation and survival of
Hodgkin's disease tumor cells. J Clin Invest, Vol.100, No.12, pp. 2961-2969, 0021-
9738
Barth, T.F.; Martin-Subero, J.I.; Joos, S.; Menz, C.K.; Hasel, C.; Mechtersheimer, G.;
Parwaresch, R.M.; Lichter, P.; Siebert, R. & Mooller, P. (2003). Gains of 2p involving
the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells
of classical Hodgkin lymphoma. Blood, Vol.101, No.9, pp. 3681-3686, 0006-4971
Bartlett, N.L.; Younes, A.; Carabasi, M.H.; Forero, A.; Rosenblatt, J.D.; Leonard, J.P.;
Bernstein, S.H.; Bociek, R.G.; Lorenz, J.M.; Hart, B.W. & Barton, J. (2008). A phase 1
multidose study of SGN-30 immunotherapy in patients with refractory or recurrent
CD30+ hematologic malignancies. Blood, Vol.111, No.4, pp. 1848-1854, 0006-4971,
0006-4971
Baumforth, K.R.; Birgersdotter, A.; Reynolds, G.M.; Wei, W.; Kapatai, G.; Flavell, J.R.; Kalk,
E.; Piper, K.; Lee, S.; Machado, L.; Hadley, K.; Sundblad, A.; Sjoberg, J.; Bjorkholm,
M.; Porwit, A.A.; Yap, L.F.; Teo, S.; Grundy, R.G.; Young, L.S.; Ernberg, I.;
Woodman, C.B. & Murray, P.G. (2008). Expression of the Epstein-Barr virus-
encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells
mediates Up-regulation of CCL20 and the migration of regulatory T cells. Am J
Pathol, Vol.173, No.1, pp. 195-204, 1525-2191
Berke, G. (1995). The CTL's kiss of death. Cell, Vol.81, No.1, pp. 9-12, 0092-8674
Bladergroen, B.A.; Meijer, C.J.; ten Berge, R.L.; Hack, C.E.; Muris, J.J.; Dukers, D.F.; Chott, A.;
Kazama, Y.; Oudejans, J.J.; van Berkum, O. & Kummer, J.A. (2002). Expression of
the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-
Hodgkin and Hodgkin lymphoma: a novel protective mechanism for tumor cells to
circumvent the immune system? Blood, Vol.99, No.1, pp. 232-237.
Blanchard, D.A.; Affredou, M.T. & Vazquez, A. (1997). Modulation of the p27kip1 cyclin-
dependent kinase inhibitor expression during IL-4-mediated human B cell
activation. J Immunol, Vol.158, No.7, pp. 3054-3061, 0022-1767
Bollard, C.M.; Aguilar, L.; Straathof, K.C.; Gahn, B.; Huls, M.H.; Rousseau, A.; Sixbey, J.;
Gresik, M.V.; Carrum, G.; Hudson, M.; Dilloo, D.; Gee, A.; Brenner, M.K.; Rooney,
C.M. & Heslop, H.E. (2004). Cytotoxic T lymphocyte therapy for Epstein-Barr
virus+ Hodgkin's disease. J Exp Med, Vol.200, No.12, pp. 1623-1633, 0022-1007
Borchmann, P.; Schnell, R.; Fuss, I.; Manzke, O.; Davis, T.; Lewis, L.D.; Behnke, D.;
Wickenhauser, C.; Schiller, P.; Diehl, V. & Engert, A. (2002). Phase 1 trial of the
novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma.
Blood, Vol.100, No.9, pp. 3101-3107, 0006-4971
Bosch Princep, R.; Lejeune, M.; Salvado Usach, M.T.; Jaen Martinez, J.; Pons Ferre, L.E. &
Alvaro Naranjo, T. (2005). Decreased number of granzyme B+ activated CD8+
cytotoxic T lymphocytes in the inflammatory background of HIV-associated
Hodgkin's lymphoma. Ann Hematol, Vol.84, No.10, pp. 661-666, 0939-5555
Bosshart, H. (2002). T helper cell activation in B-cell lymphomas. J Clin Oncol, Vol.20, No.12,
pp. 2904-2905; author reply 2905, 0732-183X
Hodgkin's Lymphoma
90
Brauninger, A.; Schmitz, R.; Bechtel, D.; Renne, C.; Hansmann, M.L. & Kuppers, R. (2006).
Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma.
Int J Cancer, Vol.118, No.8, pp. 1853-1861, 0020-7136
Brink, A.A.; Oudejans, J.J.; van den Brule, A.J.; Kluin, P.M.; Horstman, A.; Ossenkoppele,
G.J.; van Heerde, P.; Jiwa, M. & Meijer, C.J. (1998). Low p53 and high bcl-2
expression in Reed-Sternberg cells predicts poor clinical outcome for Hodgkin's
disease: involvement of apoptosis resistance? Mod Pathol, Vol.11, No.4, pp. 376-383,
0893-3952
Burnet, M. (1957). Cancer: a biological approach. III. Viruses associated with neoplastic
conditions. IV. Practical applications. Br Med J, Vol.1, No.5023, pp. 841-847, 0007-
1447
Burns, E.A. & Leventhal, E.A. (2000). Aging, immunity, and cancer. Cancer Control, Vol.7,
No.6, pp. 513-522, 1073-2748
Calo, V.; Migliavacca, M.; Bazan, V.; Macaluso, M.; Buscemi, M.; Gebbia, N. & Russo, A.
(2003). STAT proteins: from normal control of cellular events to tumorigenesis. J
Cell Physiol, Vol.197, No.2, pp. 157-168, 0021-9541
Camilleri-Broet, S.; Ferme, C.; Berger, F.; Lepage, E.; Bain, S.; Briere, J.; Marmey, B.; Gaulard,
P. & Audouin, J. (2004). TiA1 in advanced-stage classical Hodgkin's lymphoma: no
prognostic impact for positive tumour cells or number of cytotoxic cells. Virchows
Arch, Vol.445,N°4, pp. 344-346, 0945-6317
Campo, E.; Swerdlow, S.H.; Harris, N.L.; Pileri, S.; Stein, H. & Jaffe, E.S. (2011). The 2008
WHO classification of lymphoid neoplasms and beyond: evolving concepts and
practical applications. Blood, Vol.117, No.19, pp. 5019-5032, 1528-0020
Canellos, G.P.; Anderson, J.R.; Propert, K.J.; Nissen, N.; Cooper, M.R.; Henderson, E.S.;
Green, M.R.; Gottlieb, A. & Peterson, B.A. (1992). Chemotherapy of advanced
Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J
Med, Vol.327, No.21, pp. 1478-1484, 0028-4793
Carbone, A.; Gloghini, A.; Serraino, D. & Spina, M. (2009). HIV-associated Hodgkin
lymphoma. Curr Opin HIV AIDS, Vol.4, No.1, pp. 3-10, 1746-6318
Casey, T.T.; Olson, S.J.; Cousar, J.B. & Collins, R.D. (1989). Immunophenotypes of Reed-
Sternberg cells: a study of 19 cases of Hodgkin's disease in plastic-embedded
sections. Blood, Vol.74, No.8, pp. 2624-2628, 0006-4971
Chetaille, B.; Bertucci, F.; Finetti, P.; Esterni, B.; Stamatoullas, A.; Picquenot, J.M.; Copin,
M.C.; Morschhauser, F.; Casasnovas, O.; Petrella, T.; Molina, T.; Vekhoff, A.;
Feugier, P.; Bouabdallah, R.; Birnbaum, D.; Olive, D. & Xerri, L. (2009). Molecular
profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor
microenvironment and correlations with EBV infection and outcome. Blood,
Vol.113, No.12, pp. 2765-3775, 1528-0020
Chimienti, E.; Spina, M. & Gastaldi, R. (2008). Clinical characteristics and outcome of 290
patients (pts) with Hodgkin’s disease and HIV infection (HD-HIV) in pre and
HAART (highly active antiretroviral therapy) era. . Ann Oncol Vol.9 pp. iv136
Connors, J.M. (2005). State-of-the-art therapeutics: Hodgkin's lymphoma. J Clin Oncol,
Vol.23, No.26, pp. 6400-6408, 0732-183X
Connors, J.M. (2011). Hodgkin's lymphoma--the great teacher. N Engl J Med, Vol.365, No.3,
pp. 264-265, 1533-4406
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
91
Curiel, T.J.; Coukos, G.; Zou, L.; Alvarez, X.; Cheng, P.; Mottram, P.; Evdemon-Hogan, M.;
Conejo-Garcia, J.R.; Zhang, L.; Burow, M.; Zhu, Y.; Wei, S.; Kryczek, I.; Daniel, B.;
Gordon, A.; Myers, L.; Lackner, A.; Disis, M.L.; Knutson, K.L.; Chen, L. & Zou, W.
(2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters
immune privilege and predicts reduced survival. Nat Med, Vol.10, No.9, pp. 942-
949, 1078-8956
Davies, F.E.; Raje, N.; Hideshima, T.; Lentzsch, S.; Young, G.; Tai, Y.T.; Lin, B.; Podar, K.;
Gupta, D.; Chauhan, D.; Treon, S.P.; Richardson, P.G.; Schlossman, R.L.; Morgan,
G.J.; Muller, G.W.; Stirling, D.I. & Anderson, K.C. (2001). Thalidomide and
immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple
myeloma. Blood, Vol.98, No.1, pp. 210-216, 0006-4971
de la Cruz-Merino, L.; Grande-Pulido, E.; Albero-Tamarit, A. & Codes-Manuel de Villena,
M.E. (2008). Cancer and immune response: old and new evidence for future
challenges. Oncologist, Vol.13, No.12, pp. 1246-1254, 1549-490X
de Visser, K.E. & Kast, W.M. (1999). Effects of TGF-beta on the immune system: implications
for cancer immunotherapy. Leukemia, Vol.13, No.8, pp. 1188-1199, 0887-6924
Deutsch, Y.E.; Tadmor, T.; Podack, E.R. & Rosenblatt, J.D. (2011). CD30: an important new
target in hematologic malignancies. Leuk Lymphoma, Vol.52, No.9, pp. 1641-1654,
1029-2403
Devilard, E.; Bertucci, F.; Trempat, P.; Bouabdallah, R.; Loriod, B.; Giaconia, A.; Brousset, P.;
Granjeaud, S.; Nguyen, C.; Birnbaum, D.; Birg, F.; Houlgatte, R. & Xerri, L. (2002).
Gene expression profiling defines molecular subtypes of classical Hodgkin's
disease. Oncogene, Vol.21, No.19, pp. 3095-3102, 0950-9232
Dharnidharka, V.R.; Douglas, V.K.; Hunger, S.P. & Fennell, R.S. (2004). Hodgkin's
lymphoma after post-transplant lymphoproliferative disease in a renal transplant
recipient. Pediatr Transplant, Vol.8, No.1, pp. 87-90, 1397-3142
Diehl, V.; Franklin, J.; Pfreundschuh, M.; Lathan, B.; Paulus, U.; Hasenclever, D.; Tesch, H.;
Herrmann, R.; Dorken, B.; Muller-Hermelink, H.K.; Duhmke, E. & Loeffler, M.
(2003). Standard and increased-dose BEACOPP chemotherapy compared with
COPP-ABVD for advanced Hodgkin's disease. N Engl J Med, Vol.348, No.24, pp.
2386-2395, 1533-4406
Diehl, V.; Sextro, M.; Franklin, J.; Hansmann, M.L.; Harris, N.; Jaffe, E.; Poppema, S.; Harris,
M.; Franssila, K.; van Krieken, J.; Marafioti, T.; Anagnostopoulos, I. & Stein, H.
(1999). Clinical presentation, course, and prognostic factors in lymphocyte-
predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease:
report from the European Task Force on Lymphoma Project on Lymphocyte-
Predominant Hodgkin's Disease. J Clin Oncol, Vol.17, No.3, pp. 776-783, 0732-183X
Diehl, V.; Thomas, R.K. & Re, D. (2004). Part II: Hodgkin's lymphoma--diagnosis and
treatment. Lancet Oncol, Vol.5, No.1, pp. 19-26, 1470-2045
Dutton, A.; Reynolds, G.M.; Dawson, C.W.; Young, L.S. & Murray, P.G. (2005). Constitutive
activation of phosphatidyl-inositide 3 kinase contributes to the survival of
Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR.
J Pathol, Vol.205, No.4, pp. 498-506, 0022-3417
Eberle, F.C.; Rodriguez-Canales, J.; Wei, L.; Hanson, J.C.; Killian, J.K.; Sun, H.W.; Adams,
L.G.; Hewitt, S.M.; Wilson, W.H.; Pittaluga, S.; Meltzer, P.S.; Staudt, L.M.; Emmert-
Buck, M.R. & Jaffe, E.S. (2011). Methylation profiling of mediastinal gray zone
Hodgkin's Lymphoma
92
lymphoma reveals a distinctive signature with elements shared by classical
Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma.
Haematologica, Vol.96, No.4, pp. 558-566, 1592-8721
Ekstrand, B.C.; Lucas, J.B.; Horwitz, S.M.; Fan, Z.; Breslin, S.; Hoppe, R.T.; Natkunam, Y.;
Bartlett, N.L. & Horning, S.J. (2003). Rituximab in lymphocyte-predominant
Hodgkin disease: results of a phase 2 trial. Blood, Vol.101, No.11, pp. 4285-4289,
0006-4971
Emmerich, F.; Meiser, M.; Hummel, M.; Demel, G.; Foss, H.D.; Jundt, F.; Mathas, S.;
Krappmann, D.; Scheidereit, C.; Stein, H. & Dorken, B. (1999). Overexpression of I
kappa B alpha without inhibition of NF-kappaB activity and mutations in the I
kappa B alpha gene in Reed-Sternberg cells. Blood, Vol.94, No.9, pp. 3129-3134,
0006-4971
Emmerich, F.; Theurich, S.; Hummel, M.; Haeffker, A.; Vry, M.S.; Dohner, K.; Bommert, K.;
Stein, H. & Dorken, B. (2003). Inactivating I kappa B epsilon mutations in
Hodgkin/Reed-Sternberg cells. J Pathol, Vol.201, No.3, pp. 413-420, 0022-3417
Engert, A.; Plutschow, A.; Eich, H.T.; Lohri, A.; Dorken, B.; Borchmann, P.; Berger, B.; Greil,
R.; Willborn, K.C.; Wilhelm, M.; Debus, J.; Eble, M.J.; Sokler, M.; Ho, A.; Rank, A.;
Ganser, A.; Trumper, L.; Bokemeyer, C.; Kirchner, H.; Schubert, J.; Kral, Z.; Fuchs,
M.; Muller-Hermelink, H.K.; Muller, R.P. & Diehl, V. (2010). Reduced treatment
intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med, Vol.363,
No.7, pp. 640-652, 1533-4406
Falini, B.; Bolognesi, A.; Flenghi, L.; Tazzari, P.L.; Broe, M.K.; Stein, H.; Durkop, H.; Aversa,
F.; Corneli, P.; Pizzolo, G. & et al. (1992). Response of refractory Hodgkin's disease
to monoclonal anti-CD30 immunotoxin. Lancet, Vol.339, No.8803, pp. 1195-1196,
0140-6736
Falini, B.; Pileri, S.; Stein, H.; Dieneman, D.; Dallenbach, F.; Delsol, G.; Minelli, O.; Poggi, S.;
Martelli, M.F.; Pallesen, G. & et al. (1990). Variable expression of leucocyte-common
(CD45) antigen in CD30 (Ki1)-positive anaplastic large-cell lymphoma: implications
for the differential diagnosis between lymphoid and nonlymphoid malignancies.
Hum Pathol, Vol.21, No.6, pp. 624-629, 0046-8177
Falini, B.; Stein, H.; Pileri, S.; Canino, S.; Farabbi, R.; Martelli, M.F.; Grignani, F.; Fagioli, M.;
Minelli, O.; Ciani, C. & et al. (1987). Expression of lymphoid-associated antigens on
Hodgkin's and Reed-Sternberg cells of Hodgkin's disease. An immunocytochemical
study on lymph node cytospins using monoclonal antibodies. Histopathology,
Vol.11, No.12, pp. 1229-1242, 0309-0167
Famularo, G.; De Simone, C.; Tzantzoglou, S. & Trinchieri, V. (1994). Apoptosis, anti-
apoptotic compounds and TNF-alpha release. Immunol Today, Vol.15, No.10, pp.
495-496, 0167-5699
Farrell, K. & Jarrett, R.F. (2011). The molecular pathogenesis of Hodgkin lymphoma.
Histopathology, Vol.58, No.1, pp. 15-25, 1365-2559
Filippa, D.A.; Ladanyi, M.; Wollner, N.; Straus, D.J.; O'Brien, J.P.; Portlock, C.; Gangi, M. &
Sun, M. (1996). CD30 (Ki-1)-positive malignant lymphomas: clinical,
immunophenotypic, histologic, and genetic characteristics and differences with
Hodgkin's disease. Blood, Vol.87, No.7, pp. 2905-2917, 0006-4971
Fischer, M.; Juremalm, M.; Olsson, N.; Backlin, C.; Sundstrom, C.; Nilsson, K.; Enblad, G. &
Nilsson, G. (2003). Expression of CCL5/RANTES by Hodgkin and Reed-Sternberg
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
93
cells and its possible role in the recruitment of mast cells into lymphomatous tissue.
Int J Cancer, Vol.107, No.2, pp. 197-201, 0020-7136
Fontenot, J.D.; Gavin, M.A. & Rudensky, A.Y. (2003). Foxp3 programs the development and
function of CD4+CD25+ regulatory T cells. Nat Immunol, Vol.4, No.4, pp. 330-336,
Formenti, S.C. & Demaria, S. (2009). Systemic effects of local radiotherapy. Lancet Oncol,
Vol.10, No.7, pp. 718-726, 1474-5488
Foss, H.D.; Reusch, R.; Demel, G.; Lenz, G.; Anagnostopoulos, I.; Hummel, M. & Stein, H.
(1999). Frequent expression of the B-cell-specific activator protein in Reed-
Sternberg cells of classical Hodgkin's disease provides further evidence for its B-cell
origin. Blood, Vol.94, No.9, pp. 3108-3113, 0006-4971
Foyil, K.V. & Bartlett, N.L. (2010). Anti-CD30 Antibodies for Hodgkin lymphoma. Curr
Hematol Malig Rep, Vol.5, No.3, pp. 140-147, 1558-822X
Friedberg, J.W. (2011). Hodgkin lymphoma: answers take time! Blood, Vol.117, No.20, pp.
5274-5276, 1528-0020
Frisan, T.; Sjoberg, J.; Dolcetti, R.; Boiocchi, M.; De Re, V.; Carbone, A.; Brautbar, C.; Battat,
S.; Biberfeld, P.; Eckman, M. & et al. (1995). Local suppression of Epstein-Barr virus
(EBV)-specific cytotoxicity in biopsies of EBV-positive Hodgkin's disease. Blood,
Vol.86, No.4, pp. 1493-1501, 0006-4971
Gallamini, A.; Hutchings, M.; Rigacci, L.; Specht, L.; Merli, F.; Hansen, M.; Patti, C.; Loft, A.;
Di Raimondo, F.; D'Amore, F.; Biggi, A.; Vitolo, U.; Stelitano, C.; Sancetta, R.;
Trentin, L.; Luminari, S.; Iannitto, E.; Viviani, S.; Pierri, I. & Levis, A. (2007). Early
interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is
prognostically superior to international prognostic score in advanced-stage
Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol,
Vol.25, No.24, pp. 3746-3752, 1527-7755
Garcia, J.F.; Camacho, F.I.; Morente, M.; Fraga, M.; Montalban, C.; Alvaro, T.; Bellas, C.;
Castano, A.; Diez, A.; Flores, T.; Martin, C.; Martinez, M.A.; Mazorra, F.;
Menarguez, J.; Mestre, M.J.; Mollejo, M.; Saez, A.I.; Sanchez, L. & Piris, M.A. (2003).
Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor
suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays.
Blood, Vol.101, No.2, pp. 681-689, 0006-4971
Garcia, J.F.; Villuendas, R.; Algara, P.; Saez, A.I.; Sanchez-Verde, L.; Martinez-Montero, J.C.;
Martinez, P. & Piris, M.A. (1999). Loss of p16 protein expression associated with
methylation of the p16INK4A gene is a frequent finding in Hodgkin's disease. Lab
Invest, Vol.79, No.12, pp. 1453-1459, 0023-6837
Gaulard, P.; Swerdlow, S.; Harris, S. & al., e. (2008). Other iatrogenic
immunodeficiencyassociated lymphoproliferative disorders. In: World Health
Organization Classification of Tumours, Pathology and Genetics of Tumours of
Haematopoietic and Lymphoid Tissues., Swerdlow SH C.E., Harris NL, et al. (eds)
(eds),350-351. IARC Press Lyon
Gerdes, J.; Van Baarlen, J.; Pileri, S.; Schwarting, R.; Van Unnik, J.A. & Stein, H. (1987).
Tumor cell growth fraction in Hodgkin's disease. Am J Pathol, Vol.128, No.3, pp.
390-393, 0002-9440
Gonthier, M.; Llobera, R.; Arnaud, J. & Rubin, B. (2004). Self-reactive T cell receptor-reactive
CD8+ T cells inhibit T cell lymphoma growth in vivo. J Immunol, Vol.173, No.11,
pp. 7062-7069, 0022-1767
Hodgkin's Lymphoma
94
Goyal, R.K.; McEvoy, L. & Wilson, D.B. (1996). Hodgkin disease after renal transplantation
in childhood. J Pediatr Hematol Oncol, Vol.18, No.4, pp. 392-395, 1077-4114
Green, T.P.; Fennell, M.; Whittaker, R.; Curwen, J.; Jacobs, V.; Allen, J.; Logie, A.;
Hargreaves, J.; Hickinson, D.M.; Wilkinson, R.W.; Elvin, P.; Boyer, B.; Carragher,
N.; Ple, P.A.; Bermingham, A.; Holdgate, G.A.; Ward, W.H.; Hennequin, L.F.;
Davies, B.R. & Costello, G.F. (2009). Preclinical anticancer activity of the potent, oral
Src inhibitor AZD0530. Mol Oncol, Vol.3, No.3, pp. 248-261, 1574-7891
Grogg, K.L.; Miller, R.F. & Dogan, A. (2007). HIV infection and lymphoma. J Clin Pathol,
Vol.60, No.12, pp. 1365-1372, 1472-4146
Gruss, H.J.; Brach, M.A.; Drexler, H.G.; Bonifer, R.; Mertelsmann, R.H. & Herrmann, F.
(1992). Expression of cytokine genes, cytokine receptor genes, and transcription
factors in cultured Hodgkin and Reed-Sternberg cells. Cancer Res, Vol.52, No.12, pp.
3353-3360, 0008-5472
Guenova, M.; Rassidakis, G.Z.; Gorgoulis, V.G.; Angelopoulou, M.K.; Siakantaris, M.R.;
Kanavaros, P.; Pangalis, G.A. & Kittas, C. (1999). p16INK4A is regularly expressed
in Hodgkin's disease: comparison with retinoblastoma, p53 and MDM2 protein
status, and the presence of Epstein-Barr virus. Mod Pathol, Vol.12, No.11, pp. 1062-
1071, 0893-3952
Hagemann, T.; Lawrence, T.; McNeish, I.; Charles, K.A.; Kulbe, H.; Thompson, R.G.;
Robinson, S.C. & Balkwill, F.R. (2008). "Re-educating" tumor-associated
macrophages by targeting NF-kappaB. J Exp Med, Vol.205, No.6, pp. 1261-1268,
1540-9538
Hahne, M.; Renno, T.; Schroeter, M.; Irmler, M.; French, L.; Bornard, T.; MacDonald, H.R. &
Tschopp, J. (1996). Activated B cells express functional Fas ligand. Eur J Immunol,
Vol.26, No.3, pp. 721-724, 0014-2980
Hanamoto, H.; Nakayama, T.; Miyazato, H.; Takegawa, S.; Hieshima, K.; Tatsumi, Y.;
Kanamaru, A. & Yoshie, O. (2004). Expression of CCL28 by Reed-Sternberg cells
defines a major subtype of classical Hodgkin's disease with frequent infiltration of
eosinophils and/or plasma cells. Am J Pathol, Vol.164, No.3, pp. 997-1006, 0002-9440
Haque, T.; Wilkie, G.M.; Jones, M.M.; Higgins, C.D.; Urquhart, G.; Wingate, P.; Burns, D.;
McAulay, K.; Turner, M.; Bellamy, C.; Amlot, P.L.; Kelly, D.; MacGilchrist, A.;
Gandhi, M.K.; Swerdlow, A.J.; Crawford, D.H. (2007). Allogeneic cytotoxic T cell
therapy for EBV-positive posttransplantation lymphoproliferative disease: results
of a phase 2 multicenter clinical trial. Blood, Vol. 110, No.4, pp 1123-31, 0006-4971
Harris, N.L.; Jaffe, E.S.; Diebold, J.; Flandrin, G.; Muller-Hermelink, H.K.; Vardiman, J.;
Lister, T.A. & Bloomfield, C.D. (2000). The World Health Organization
classification of neoplastic diseases of the haematopoietic and lymphoid tissues:
Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia,
November 1997. Histopathology, Vol.36, No.1, pp. 69-86, 0309-0167
Harris, N.L.; Jaffe, E.S.; Stein, H.; Banks, P.M.; Chan, J.K.; Cleary, M.L.; Delsol, G.; De Wolf-
Peeters, C.; Falini, B.; Gatter, K.C. & et al. (1994). A revised European-American
classification of lymphoid neoplasms: a proposal from the International Lymphoma
Study Group. Blood, Vol.84, No.5, pp. 1361-1392, 0006-4971
Hartmann, F.; Renner, C.; Jung, W.; da Costa, L.; Tembrink, S.; Held, G.; Sek, A.; Konig, J.;
Bauer, S.; Kloft, M. & Pfreundschuh, M. (2001). Anti-CD16/CD30 bispecific
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
95
antibody treatment for Hodgkin's disease: role of infusion schedule and
costimulation with cytokines. Clin Cancer Res, Vol.7, No.7, pp. 1873-1881, 1078-0432
Hartmann, F.; Renner, C.; Jung, W.; Deisting, C.; Juwana, M.; Eichentopf, B.; Kloft, M. &
Pfreundschuh, M. (1997). Treatment of refractory Hodgkin's disease with an anti-
CD16/CD30 bispecific antibody. Blood, Vol.89, No.6, pp. 2042-2047, 0006-4971
Hasenclever, D. & Diehl, V. (1998). A prognostic score for advanced Hodgkin's disease.
International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J
Med, Vol.339, No.21, pp. 1506-1514, 0028-4793
Haynes, N.M.; van der Most, R.G.; Lake, R.A. & Smyth, M.J. (2008). Immunogenic anti-
cancer chemotherapy as an emerging concept. Curr Opin Immunol, Vol.20, No.5, pp.
545-557, 0952-7915
Hertel, C.B.; Zhou, X.G.; Hamilton-Dutoit, S.J. & Junker, S. (2002). Loss of B cell identity
correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-
Sternberg cells of classical Hodgkin lymphoma. Oncogene, Vol.21, No.32, pp. 4908-
4920, 0950-9232
Hinz, M.; Lemke, P.; Anagnostopoulos, I.; Hacker, C.; Krappmann, D.; Mathas, S.; Dorken,
B.; Zenke, M.; Stein, H. & Scheidereit, C. (2002). Nuclear factor kappaB-dependent
gene expression profiling of Hodgkin's disease tumor cells, pathogenetic
significance, and link to constitutive signal transducer and activator of
transcription 5a activity. J Exp Med, Vol.196, No.5, pp. 605-617, 0022-1007
Hinz, M.; Loser, P.; Mathas, S.; Krappmann, D.; Dorken, B. & Scheidereit, C. (2001).
Constitutive NF-kappaB maintains high expression of a characteristic gene
network, including CD40, CD86, and a set of antiapoptotic genes in
Hodgkin/Reed-Sternberg cells. Blood, Vol.97, No.9, pp. 2798-2807, 0006-4971
Hiscox, S.; Barrett-Lee, P. & Nicholson, R.I. (2011). Therapeutic targeting of tumor-stroma
interactions. Expert Opin Ther Targets, Vol.15, No.5, pp. 609-621, 1744-7631
Hislop, A.D.; Annels, N.E.; Gudgeon, N.H.; Leese, A.M. & Rickinson, A.B. (2002). Epitope-
specific evolution of human CD8(+) T cell responses from primary to persistent
phases of Epstein-Barr virus infection. J Exp Med, Vol.195, No.7, pp. 893-905, 0022-
1007
Hnatkova, M.; Mocikova, H.; Trneny, M. & Zivny, J. (2009). The biological environment of
Hodgkin's lymphoma and the role of the chemokine CCL17/TARC. Prague Med
Rep, Vol.110, No.1, pp. 35-41, 1214-6994
Hong, S.Y.; Yoon, W.H.; Park, J.H.; Kang, S.G.; Ahn, J.H. & Lee, T.H. (2000). Involvement of
two NF-kappa B binding elements in tumor necrosis factor alpha -, CD40-, and
epstein-barr virus latent membrane protein 1-mediated induction of the cellular
inhibitor of apoptosis protein 2 gene. J Biol Chem, Vol.275, No.24, pp. 18022-18028,
0021-9258
Hori, S.; Nomura, T. & Sakaguchi, S. (2003). Control of regulatory T cell development by the
transcription factor Foxp3. Science, Vol.299, No.5609, pp. 1057-1061, 0036-8075
Horie, R.; Watanabe, T.; Morishita, Y.; Ito, K.; Ishida, T.; Kanegae, Y.; Saito, I.; Higashihara,
M.; Mori, S.; Kadin, M.E. & Watanabe, T. (2002). Ligand-independent signaling by
overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg
cells. Oncogene, Vol.21, No.16, pp. 2493-2503, 0950-9232
Hodgkin's Lymphoma
96
Hsu, S.M.; Krupen, K. & Lachman, L.B. (1989). Heterogeneity of interleukin 1 production in
cultured Reed-Sternberg cell lines HDLM-1, HDLM-1d, and KM-H2. Am J Pathol,
Vol.135, No.1, pp. 33-38, 0002-9440
Hutchings, M.; Mikhaeel, N.G.; Fields, P.A.; Nunan, T. & Timothy, A.R. (2005). Prognostic
value of interim FDG-PET after two or three cycles of chemotherapy in Hodgkin
lymphoma. Ann Oncol, Vol.16, No.7, pp. 1160-1168, 0923-7534
Ichim, C.V. (2005). Revisiting immunosurveillance and immunostimulation: Implications for
cancer immunotherapy. J Transl Med, Vol.3, No.1, pp. 8, 1479-5876, 1479-5876
Ikeda, H.; Old, L.J. & Schreiber, R.D. (2002). The roles of IFN gamma in protection against
tumor development and cancer immunoediting. Cytokine Growth Factor Rev, Vol.13,
No.2, pp. 95-109, 1359-6101
Inoki, K.; Li, Y.; Zhu, T.; Wu, J. & Guan, K.L. (2002). TSC2 is phosphorylated and inhibited
by Akt and suppresses mTOR signalling. Nat Cell Biol, Vol.4, No.9, pp. 648-657,
1465-7392
Inoue, J.; Ishida, T.; Tsukamoto, N.; Kobayashi, N.; Naito, A.; Azuma, S. & Yamamoto, T.
(2000). Tumor necrosis factor receptor-associated factor (TRAF) family: adapter
proteins that mediate cytokine signaling. Exp Cell Res, Vol.254, No.1, pp. 14-24,
0014-4827
Izban, K.F.; Ergin, M.; Huang, Q.; Qin, J.Z.; Martinez, R.L.; Schnitzer, B.; Ni, H.; Nickoloff,
B.J. & Alkan, S. (2001). Characterization of NF-kappaB expression in Hodgkin's
disease: inhibition of constitutively expressed NF-kappaB results in spontaneous
caspase-independent apoptosis in Hodgkin and Reed-Sternberg cells. Mod Pathol,
Vol.14, No.4, pp. 297-310, 0893-3952
Jarrett, R.F. (2002). Viruses and Hodgkin's lymphoma. Ann Oncol, Vol.13 Suppl 1, pp. 23-29,
0923-7534
Jarrett, R.F. (2006). Viruses and lymphoma/leukaemia. J Pathol, Vol.208, No.2, pp. 176-186,
0022-3417
Joos, S.; Granzow, M.; Holtgreve-Grez, H.; Siebert, R.; Harder, L.; Martin-Subero, J.I.; Wolf,
J.; Adamowicz, M.; Barth, T.F.; Lichter, P. & Jauch, A. (2003). Hodgkin's lymphoma
cell lines are characterized by frequent aberrations on chromosomes 2p and 9p
including REL and JAK2. Int J Cancer, Vol.103, No.4, pp. 489-495, 0020-7136
Joos, S.; Menz, C.K.; Wrobel, G.; Siebert, R.; Gesk, S.; Ohl, S.; Mechtersheimer, G.; Trumper,
L.; Moller, P.; Lichter, P. & Barth, T.F. (2002). Classical Hodgkin lymphoma is
characterized by recurrent copy number gains of the short arm of chromosome 2.
Blood, Vol.99, No.4, pp. 1381-1387, 0006-4971
Jourdan, M.; De Vos, J.; Mechti, N. & Klein, B. (2000). Regulation of Bcl-2-family proteins in
myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha
and insulin-like growth factor 1. Cell Death Differ, Vol.7, No.12, pp. 1244-1252, 1350-
9047
Jungnickel, B.; Staratschek-Jox, A.; Brauninger, A.; Spieker, T.; Wolf, J.; Diehl, V.; Hansmann,
M.L.; Rajewsky, K. & Kuppers, R. (2000). Clonal deleterious mutations in the
IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma. J Exp Med,
Vol.191, No.2, pp. 395-402, 0022-1007
Juszczynski, P.; Ouyang, J.; Monti, S.; Rodig, S.J.; Takeyama, K.; Abramson, J.; Chen, W.;
Kutok, J.L.; Rabinovich, G.A. & Shipp, M.A. (2007). The AP1-dependent secretion
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
97
of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin
lymphoma. Proc Natl Acad Sci U S A, Vol.104, No.32, pp. 13134-13139, 0027-8424
Kamper, P.; Bendix, K.; Hamilton-Dutoit, S.; Honore, B.; Nyengaard, J.R. & d'Amore, F.
(2011). Tumor-infiltrating macrophages correlate with adverse prognosis and
Epstein-Barr virus status in classical Hodgkin's lymphoma. Haematologica, Vol.96,
No.2, pp. 269-276, 1592-8721
Kanavaros, P.; Stefanaki, K.; Vlachonikolis, J.; Eliopoulos, G.; Kakolyris, S.; Rontogianni, D.;
Gorgoulis, V. & Georgoulias, V. (2000). Expression of p53, p21/waf1, bcl-2, bax, Rb
and Ki67 proteins in Hodgkin's lymphomas. Histol Histopathol, Vol.15, No.2, pp.
445-453, 0213-3911
Kanavaros, P.; Vlychou, M.; Stefanaki, K.; Rontogianni, D.; Gaulard, P.; Pantelidaki, E.; Zois,
M.; Darivianaki, K.; Georgoulias, V.; Boulland, M.L.; Gorgoulis, V. & Kittas, C.
(1999). Cytotoxic protein expression in non-Hodgkin's lymphomas and Hodgkin's
disease. Anticancer Res, Vol.19, No.2A, pp. 1209-1216, 0250-7005
Kanzler, H.; Kuppers, R.; Hansmann, M.L. & Rajewsky, K. (1996). Hodgkin and Reed-
Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor
clone derived from (crippled) germinal center B cells. J Exp Med, Vol.184, No.4, pp.
1495-1505, 0022-1007
Kapatai, G. & Murray, P. (2007). Contribution of the Epstein Barr virus to the molecular
pathogenesis of Hodgkin lymphoma. J Clin Pathol, Vol.60, No.12, pp. 1342-1349,
1472-4146
Karin, M. & Greten, F.R. (2005). NF-kappaB: linking inflammation and immunity to cancer
development and progression. Nat Rev Immunol, Vol.5, No.10, pp. 749-759, 1474-
1733
Karube, K.; Ohshima, K.; Tsuchiya, T.; Yamaguchi, T.; Kawano, R.; Suzumiya, J.;
Utsunomiya, A.; Harada, M. & Kikuchi, M. (2004). Expression of FoxP3, a key
molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma
cells. Br J Haematol, Vol.126, No.1, pp. 81-84, 0007-1048
Kasamon, Y.L.; Ambinder, R.F. (2008). Immunotherapies for Hodgkin´s lymphoma. Crit Rev
Oncol Hematol, Vol. 66, No.2, pp 135-144, 1040-8428
Kater, A.P.; Evers, L.M.; Remmerswaal, E.B.; Jaspers, A.; Oosterwijk, M.F.; van Lier, R.A.;
van Oers, M.H. & Eldering, E. (2004). CD40 stimulation of B-cell chronic
lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid
expression and cells remain susceptible to autologous cytotoxic T-lymphocyte
attack. Br J Haematol, Vol.127, No.4, pp. 404-415, 0007-1048
Kato, M.; Sanada, M.; Kato, I.; Sato, Y.; Takita, J.; Takeuchi, K.; Niwa, A.; Chen, Y.; Nakazaki,
K.; Nomoto, J.; Asakura, Y.; Muto, S.; Tamura, A.; Iio, M.; Akatsuka, Y.; Hayashi, Y.;
Mori, H.; Igarashi, T.; Kurokawa, M.; Chiba, S.; Mori, S.; Ishikawa, Y.; Okamoto, K.;
Tobinai, K.; Nakagama, H.; Nakahata, T.; Yoshino, T.; Kobayashi, Y. & Ogawa, S.
(2009). Frequent inactivation of A20 in B-cell lymphomas. Nature, Vol.459, No.7247,
pp. 712-716, 1476-4687
Kennedy, G.; Komano, J. & Sugden, B. (2003). Epstein-Barr virus provides a survival factor
to Burkitt's lymphomas. Proc Natl Acad Sci U S A, Vol.100, No.24, pp. 14269-14274,
0027-8424
Hodgkin's Lymphoma
98
Khan, G. (2006). Epstein-Barr virus, cytokines, and inflammation: a cocktail for the
pathogenesis of Hodgkin's lymphoma? Exp Hematol, Vol.34, No.4, pp. 399-406,
0301-472X
Kilger, E.; Kieser, A.; Baumann, M. & Hammerschmidt, W. (1998). Epstein-Barr virus-
mediated B-cell proliferation is dependent upon latent membrane protein 1, which
simulates an activated CD40 receptor. Embo J, Vol.17, No.6, pp. 1700-1709, 0261-
4189
Kim, T.H.; Kim, H.I.; Soung, Y.H.; Shaw, L.A. & Chung, J. (2009). Integrin (alpha6beta4)
signals through Src to increase expression of S100A4, a metastasis-promoting
factor: implications for cancer cell invasion. Mol Cancer Res, Vol.7, No.10, pp. 1605-
1612, 1557-3125
Klimm, B.; Schnell, R.; Diehl, V. & Engert, A. (2005). Current treatment and immunotherapy
of Hodgkin's lymphoma. Haematologica, Vol.90, No.12, pp. 1680-1692, 1592-8721
Knight, J.S.; Tsodikov, A.; Cibrik, D.M.; Ross, C.W.; Kaminski, M.S. & Blayney, D.W. (2009).
Lymphoma after solid organ transplantation: risk, response to therapy, and
survival at a transplantation center. J Clin Oncol, Vol.27, No.20, pp. 3354-3362, 1527-
7755
Kolar, Z.; Flavell, J.R.; Ehrmann, J., Jr.; Rihakova, P.; Macak, J.; Lowe, D.; Crocker, J.;
Vojtesek, B.; Young, L.S. & Murray, P.G. (2000). Apoptosis of malignant cells in
Hodgkin's disease is related to expression of the cdk inhibitor p27KIP1. J Pathol,
Vol.190, No.5, pp. 604-612, 0022-3417
Korkolopoulou, P.; Cordell, J.; Jones, M.; Kaklamanis, L.; Tsenga, A.; Gatter, K.C. & Mason,
D.Y. (1994). The expression of the B-cell marker mb-1 (CD79a) in Hodgkin's
disease. Histopathology, Vol.24, No.6, pp. 511-515, 0309-0167
Kreitman, R.J.; Wilson, W.H.; White, J.D.; Stetler-Stevenson, M.; Jaffe, E.S.; Giardina, S.;
Waldmann, T.A. & Pastan, I. (2000). Phase I trial of recombinant immunotoxin anti-
Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol,
Vol.18, No.8, pp. 1622-1636, 0732-183X
Krishnamurthy, S.; Hassan, A.; Frater, J.L.; Paessler, M.E. & Kreisel, F.H. (2010). Pathologic
and clinical features of Hodgkin lymphoma--like posttransplant
lymphoproliferative disease. Int J Surg Pathol, Vol.18, No.4, pp. 278-285, 1940-2465
Kube, D.; Holtick, U.; Vockerodt, M.; Ahmadi, T.; Haier, B.; Behrmann, I.; Heinrich, P.C.;
Diehl, V. & Tesch, H. (2001). STAT3 is constitutively activated in Hodgkin cell lines.
Blood, Vol.98, No.3, pp. 762-770, 0006-4971
Kupper, M.; Joos, S.; von Bonin, F.; Daus, H.; Pfreundschuh, M.; Lichter, P. & Trumper, L.
(2001). MDM2 gene amplification and lack of p53 point mutations in Hodgkin and
Reed-Sternberg cells: results from single-cell polymerase chain reaction and
molecular cytogenetic studies. Br J Haematol, Vol.112, No.3, pp. 768-775, 0007-1048
Kuppers, R. (2002). Molecular biology of Hodgkin's lymphoma. Adv Cancer Res, Vol.84, pp.
277-312, 0065-230X
Kuppers, R.; Hajadi, M.; Plank, L.; Rajewsky, K. & Hansmann, M.L. (1996). Molecular Ig
gene analysis reveals that monocytoid B cell lymphoma is a malignancy of mature
B cells carrying somatically mutated V region genes and suggests that
rearrangement of the kappa-deleting element (resulting in deletion of the Ig kappa
enhancers) abolishes somatic hypermutation in the human. Eur J Immunol, Vol.26,
No.8, pp. 1794-1800, 0014-2980
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
99
Kuppers, R.; Klein, U.; Schwering, I.; Distler, V.; Brauninger, A.; Cattoretti, G.; Tu, Y.;
Stolovitzky, G.A.; Califano, A.; Hansmann, M.L. & Dalla-Favera, R. (2003).
Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene
expression profiling. J Clin Invest, Vol.111, No.4, pp. 529-537, 0021-9738
Kuppers, R.; Rajewsky, K.; Zhao, M.; Simons, G.; Laumann, R.; Fischer, R. & Hansmann,
M.L. (1994). Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from
histological sections show clonal immunoglobulin gene rearrangements and appear
to be derived from B cells at various stages of development. Proc Natl Acad Sci U S
A, Vol.91, No.23, pp. 10962-10966, 0027-8424
Kuppers, R.; Sousa, A.B.; Baur, A.S.; Strickler, J.G.; Rajewsky, K. & Hansmann, M.L. (2001).
Common germinal-center B-cell origin of the malignant cells in two composite
lymphomas, involving classical Hodgkin's disease and either follicular lymphoma
or B-CLL. Mol Med, Vol.7, No.5, pp. 285-292, 1076-1551
Lake, A.; Shield, L.A.; Cordano, P.; Chui, D.T.; Osborne, J.; Crae, S.; Wilson, K.S.; Tosi, S.;
Knight, S.J.; Gesk, S.; Siebert, R.; Hay, R.T. & Jarrett, R.F. (2009). Mutations of
NFKBIA, encoding IkappaB alpha, are a recurrent finding in classical Hodgkin
lymphoma but are not a unifying feature of non-EBV-associated cases. Int J Cancer,
Vol.125, No.6, pp. 1334-1342, 1097-0215
Lam, N. & Sugden, B. (2003). CD40 and its viral mimic, LMP1: similar means to different
ends. Cell Signal, Vol.15, No.1, pp. 9-16, 0898-6568
Lauritzen, A.F.; Moller, P.H.; Nedergaard, T.; Guldberg, P.; Hou-Jensen, K. & Ralfkiaer, E.
(1999). Apoptosis-related genes and proteins in Hodgkin's disease. Apmis, Vol.107,
No.7, pp. 636-644, 0903-4641
Lee, H.H.; Dadgostar, H.; Cheng, Q.; Shu, J. & Cheng, G. (1999). NF-kappaB-mediated up-
regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B
lymphocytes. Proc Natl Acad Sci U S A, Vol.96, No.16, pp. 9136-9141, 0027-8424
Leoncini, L.; Spina, D.; Megha, T.; Gallorini, M.; Tosi, P.; Hummel, M.; Stein, H.; Pileri, S.;
Kraft, R.; Laissue, J.A. & Cottier, H. (1997). Cell kinetics, morphology, and
molecular IgVH gene rearrangements in Hodgkin's disease. Leuk Lymphoma, Vol.26,
No.3-4, pp. 307-316, 1042-8194
Lucas, K.G.; Salzman, D.; García, A.; Sun, Q. (2004). Adoptive immunotherapy with
allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes for recurrent
EBV-positive Hodgkin disease. Cancer, Vol. 100, No 9, pp 1892-901, 0008-543X
Maggioncalda, A.; Malik, N.; Shenoy, P.; Smith, M.; Sinha, R. & Flowers, C.R. (2011).
Clinical, molecular, and environmental risk factors for hodgkin lymphoma. Adv
Hematol, Vol.2011, pp. 736261, 1687-9112
Maier, S.K. & Hammond, J.M. (2006). Role of lenalidomide in the treatment of multiple
myeloma and myelodysplastic syndrome. Ann Pharmacother, Vol.40, No.2, pp. 286-
289, 1060-0280
Malumbres, M. & Barbacid, M. (2001). To cycle or not to cycle: a critical decision in cancer.
Nat Rev Cancer, Vol.1, No.3, pp. 222-231, 1474-175X
Marafioti, T.; Hummel, M.; Foss, H.D.; Laumen, H.; Korbjuhn, P.; Anagnostopoulos, I.;
Lammert, H.; Demel, G.; Theil, J.; Wirth, T. & Stein, H. (2000). Hodgkin and reed-
sternberg cells represent an expansion of a single clone originating from a germinal
center B-cell with functional immunoglobulin gene rearrangements but defective
immunoglobulin transcription. Blood, Vol.95, No.4, pp. 1443-1450, 0006-4971
Hodgkin's Lymphoma
100
Marshall, N.A.; Christie, L.E.; Munro, L.R.; Culligan, D.J.; Johnston, P.W.; Barker, R.N. &
Vickers, M.A. (2004). Immunosuppressive regulatory T cells are abundant in the
reactive lymphocytes of Hodgkin lymphoma. Blood, Vol.103, No.5, pp. 1755-1762,
0006-4971
Martin-Subero, J.I.; Gesk, S.; Harder, L.; Sonoki, T.; Tucker, P.W.; Schlegelberger, B.; Grote,
W.; Novo, F.J.; Calasanz, M.J.; Hansmann, M.L.; Dyer, M.J. & Siebert, R. (2002).
Recurrent involvement of the REL and BCL11A loci in classical Hodgkin
lymphoma. Blood, Vol.99, No.4, pp. 1474-1477, 0006-4971
Mason, D.Y.; Banks, P.M.; Chan, J.; Cleary, M.L.; Delsol, G.; de Wolf Peeters, C.; Falini, B.;
Gatter, K.; Grogan, T.M.; Harris, N.L. & et al. (1994). Nodular lymphocyte
predominance Hodgkin's disease. A distinct clinicopathological entity. Am J Surg
Pathol, Vol.18, No.5, pp. 526-530, 0147-5185
Mathas, S.; Hinz, M.; Anagnostopoulos, I.; Krappmann, D.; Lietz, A.; Jundt, F.; Bommert, K.;
Mechta-Grigoriou, F.; Stein, H.; Dorken, B. & Scheidereit, C. (2002). Aberrantly
expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate
proliferation and synergize with NF-kappa B. Embo J, Vol.21, No.15, pp. 4104-4113,
0261-4189
Mathas, S.; Janz, M.; Hummel, F.; Hummel, M.; Wollert-Wulf, B.; Lusatis, S.;
Anagnostopoulos, I.; Lietz, A.; Sigvardsson, M.; Jundt, F.; Johrens, K.; Bommert, K.;
Stein, H. & Dorken, B. (2006). Intrinsic inhibition of transcription factor E2A by
HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in
Hodgkin lymphoma. Nat Immunol, Vol.7, No.2, pp. 207-215, 1529-2908
Medema, J.P.; de Jong, J.; Peltenburg, L.T.; Verdegaal, E.M.; Gorter, A.; Bres, S.A.; Franken,
K.L.; Hahne, M.; Albar, J.P.; Melief, C.J. & Offringa, R. (2001). Blockade of the
granzyme B/perforin pathway through overexpression of the serine protease
inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc
Natl Acad Sci U S A, Vol.98, No.20, pp. 11515-11520, 0027-8424
Messineo, C.; Jamerson, M.H.; Hunter, E.; Braziel, R.; Bagg, A.; Irving, S.G. & Cossman, J.
(1998). Gene expression by single Reed-Sternberg cells: pathways of apoptosis and
activation. Blood, Vol.91, No.7, pp. 2443-2451, 0006-4971
Metkar, S.S.; Manna, P.P.; Anand, M.; Naresh, K.N.; Advani, S.H. & Nadkarni, J.J. (2001).
CD40 Ligand--an anti-apoptotic molecule in Hodgkin's disease. Cancer Biother
Radiopharm, Vol.16, No.1, pp. 85-92, 1084-9785
Montalban, C.; Abraira, V.; Morente, M.; Acevedo, A.; Aguilera, B.; Bellas, C.; Fraga, M.; Del
Moral, R.G.; Menarguez, J.; Oliva, H.; Sanchez-Beato, M. & Piris, M.A. (2000).
Epstein-Barr virus-latent membrane protein 1 expression has a favorable influence
in the outcome of patients with Hodgkin's Disease treated with chemotherapy. Leuk
Lymphoma, Vol.39, No.5-6, pp. 563-572, 1042-8194
Montalban, C.; Garcia, J.F.; Abraira, V.; Gonzalez-Camacho, L.; Morente, M.M.; Bello, J.L.;
Conde, E.; Cruz, M.A.; Garcia-Sanz, R.; Garcia-Larana, J.; Grande, C.; Llanos, M.;
Martinez, R.; Flores, E.; Mendez, M.; Ponderos, C.; Rayon, C.; Sanchez-Godoy, P.;
Zamora, J. & Piris, M.A. (2004). Influence of biologic markers on the outcome of
Hodgkin's lymphoma: a study by the Spanish Hodgkin's Lymphoma Study Group.
J Clin Oncol, Vol.22, No.9, pp. 1664-1673, 0732-183X
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
101
Montesinos-Rongen, M.; Roers, A.; Kuppers, R.; Rajewsky, K. & Hansmann, M.L. (1999).
Mutation of the p53 gene is not a typical feature of Hodgkin and Reed-Sternberg
cells in Hodgkin's disease. Blood, Vol.94, No.5, pp. 1755-1760, 0006-4971
Morente, M.M.; Piris, M.A.; Abraira, V.; Acevedo, A.; Aguilera, B.; Bellas, C.; Fraga, M.;
Garcia-Del-Moral, R.; Gomez-Marcos, F.; Menarguez, J.; Oliva, H.; Sanchez-Beato,
M. & Montalban, C. (1997). Adverse clinical outcome in Hodgkin's disease is
associated with loss of retinoblastoma protein expression, high Ki67 proliferation
index, and absence of Epstein-Barr virus-latent membrane protein 1 expression.
Blood, Vol.90, No.6, pp. 2429-2436
Muschen, M.; Kuppers, R.; Spieker, T.; Brauninger, A.; Rajewsky, K. & Hansmann, M.L.
(2001). Molecular single-cell analysis of Hodgkin- and Reed-Sternberg cells
harboring unmutated immunoglobulin variable region genes. Lab Invest, Vol.81,
No.3, pp. 289-295, 0023-6837
Muschen, M.; Rajewsky, K.; Brauninger, A.; Baur, A.S.; Oudejans, J.J.; Roers, A.; Hansmann,
M.L. & Kuppers, R. (2000). Rare occurrence of classical Hodgkin's disease as a T cell
lymphoma. J Exp Med, Vol.191, No.2, pp. 387-394, 0022-1007
Newcom, S.R.; Kadin, M.E.; Ansari, A.A. & Diehl, V. (1988). L-428 nodular sclerosing
Hodgkin's cell secretes a unique transforming growth factor-beta active at
physiologic pH. J Clin Invest, Vol.82, No.6, pp. 1915-1921, 0021-9738
Ng, A.K.; Bernardo, M.V.; Weller, E.; Backstrand, K.; Silver, B.; Marcus, K.C.; Tarbell, N.J.;
Stevenson, M.A.; Friedberg, J.W. & Mauch, P.M. (2002). Second malignancy after
Hodgkin disease treated with radiation therapy with or without chemotherapy:
long-term risks and risk factors. Blood, Vol.100, No.6, pp. 1989-1996, 0006-4971
Nie, L.; Xu, M.; Vladimirova, A. & Sun, X.H. (2003). Notch-induced E2A ubiquitination and
degradation are controlled by MAP kinase activities. Embo J, Vol.22, No.21, pp.
5780-5792, 0261-4189
Niens, M.; Visser, L.; Nolte, I.M.; van der Steege, G.; Diepstra, A.; Cordano, P.; Jarrett, R.F.;
Te Meerman, G.J.; Poppema, S. & van den Berg, A. (2008). Serum chemokine levels
in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22. Br J
Haematol, Vol.140, No.5, pp. 527-536, 1365-2141
Nogova, L.; Reineke, T.; Brillant, C.; Sieniawski, M.; Rudiger, T.; Josting, A.; Bredenfeld, H.;
Skripnitchenko, R.; Muller, R.P.; Muller-Hermelink, H.K.; Diehl, V. & Engert, A.
(2008). Lymphocyte-predominant and classical Hodgkin's lymphoma: a
comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol,
Vol.26, No.3, pp. 434-439, 1527-7755
Obeid, M.; Panaretakis, T.; Joza, N.; Tufi, R.; Tesniere, A.; van Endert, P.; Zitvogel, L. &
Kroemer, G. (2007a). Calreticulin exposure is required for the immunogenicity of
gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ, Vol.14,
No.10, pp. 1848-1850, 1350-9047
Obeid, M.; Tesniere, A.; Ghiringhelli, F.; Fimia, G.M.; Apetoh, L.; Perfettini, J.L.; Castedo, M.;
Mignot, G.; Panaretakis, T.; Casares, N.; Metivier, D.; Larochette, N.; van Endert, P.;
Ciccosanti, F.; Piacentini, M.; Zitvogel, L. & Kroemer, G. (2007b). Calreticulin
exposure dictates the immunogenicity of cancer cell death. Nat Med, Vol.13, No.1,
pp. 54-61, 1078-8956
Ohshima, K.; Haraoka, S.; Fujiki, T.; Yoshioka, S.; Suzumiya, J.; Kanda, M. & Kikuchi, M.
(1999). Expressions of cyclin E, A, and B1 in Hodgkin and Reed-Sternberg cells: not
Hodgkin's Lymphoma
102
suppressed by cyclin-dependent kinase inhibitor p21 expression. Pathol Int, Vol.49,
No.6, pp. 506-512, 1320-5463
Ohshima, K.; Suzumiya, J.; Akamatu, M.; Takeshita, M. & Kikuchi, M. (1995). Human and
viral interleukin-10 in Hodgkin's disease, and its influence on CD4+ and CD8+ T
lymphocytes. Int J Cancer, Vol.62, No.1, pp. 5-10
Okeley, N.M.; Miyamoto, J.B.; Zhang, X.; Sanderson, R.J.; Benjamin, D.R.; Sievers, E.L.;
Senter, P.D. & Alley, S.C. (2010). Intracellular activation of SGN-35, a potent anti-
CD30 antibody-drug conjugate. Clin Cancer Res, Vol.16, No.3, pp. 888-897, 1078-
0432
Oudejans, J.J.; Jiwa, N.M.; Kummer, J.A.; Ossenkoppele, G.J.; van Heerde, P.; Baars, J.W.;
Kluin, P.M.; Kluin-Nelemans, J.C.; van Diest, P.J.; Middeldorp, J.M. & Meijer, C.J.
(1997). Activated cytotoxic T cells as prognostic marker in Hodgkin's disease. Blood,
Vol.89, No.4, pp. 1376-1382, 0006-4971
Pages, F.; Galon, J.; Dieu-Nosjean, M.C.; Tartour, E.; Sautes-Fridman, C. & Fridman, W.H.
(2010). Immune infiltration in human tumors: a prognostic factor that should not be
ignored. Oncogene, Vol.29, No.8, pp. 1093-1102, 1476-5594
Parsons, J.T.; Slack-Davis, J.; Tilghman, R. & Roberts, W.G. (2008). Focal adhesion kinase:
targeting adhesion signaling pathways for therapeutic intervention. Clin Cancer Res,
Vol.14, No.3, pp. 627-632, 1078-0432 (
Peh, S.C.; Kim, L.H. & Poppema, S. (2001). TARC, a CC chemokine, is frequently expressed
in classic Hodgkin's lymphoma but not in NLP Hodgkin's lymphoma, T-cell-rich B-
cell lymphoma, and most cases of anaplastic large cell lymphoma. Am J Surg Pathol,
Vol.25, No.7, pp. 925-929, 0147-5185
Peipp, M. & Valerius, T. (2002). Bispecific antibodies targeting cancer cells. Biochem Soc
Trans, Vol.30, No.4, pp. 507-511, 0300-5127
Pham, P.T.; Wilkinson, A.H.; Gritsch, H.A.; Pham, P.C.; Miller, J.M.; Lassman, C.R. &
Danovitch, G.M. (2002). Monotherapy with the anti-CD20 monoclonal antibody
rituximab in a kidney transplant recipient with posttransplant lymphoproliferative
disease. Transplant Proc, Vol.34, No.4, pp. 1178-1181, 0041-1345
Piccaluga, P.P.; Agostinelli, C.; Gazzola, A.; Tripodo, C.; Bacci, F.; Sabattini, E.; Sista, M.T.;
Mannu, C.; Sapienza, M.R.; Rossi, M.; Laginestra, M.A.; Sagramoso-Sacchetti, C.A.;
Righi, S. & Pileri, S.A. (2011). Pathobiology of hodgkin lymphoma. Adv Hematol,
Vol.2011, pp. 920898, 1687-9112
Pileri, S.; Sabattini, E.; Tazzari, P.L.; Gherlinzoni, F.; Zucchini, L.; Bigerna, B.; Leoncini, L.;
Rosso, R.; Stein, H. & Falini, B. (1991). Hodgkin's disease: update of findings.
Haematologica, Vol.76, No.3, pp. 175-182, 0390-6078
Pileri, S.A.; Poggi, S.; Sabattini, E.; De Vivo, A.; Falini, B. & Stein, H. (1995). Is Hodgkin's
disease a unique entity? Leuk Lymphoma, Vol.15 Suppl 1, pp. 3-6, 1042-8194
Poppema, S.; Potters, M.; Emmens, R.; Visser, L. & van den Berg, A. (1999). Immune
reactions in classical Hodgkin's lymphoma. Semin Hematol, Vol.36, No.3, pp. 253-
259, 0037-1963
Poppema, S.; Potters, M.; Visser, L. & van den Berg, A.M. (1998). Immune escape
mechanisms in Hodgkin's disease. Ann Oncol, Vol.9, No.Suppl 5, pp. S21-24, 0923-
7534
Poppema, S. & Visser, L. (1994). Absence of HLA class I expression by Reed-Sternberg cells.
Am J Pathol, Vol.145, No.1, pp. 37-41, 0002-9440
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
103
Portis, T.; Dyck, P. & Longnecker, R. (2003). Epstein-Barr Virus (EBV) LMP2A induces
alterations in gene transcription similar to those observed in Reed-Sternberg cells of
Hodgkin lymphoma. Blood, Vol.102, No.12, pp. 4166-4178, 0006-4971
Powles, T. & Bower, M. (2000). HIV-associated Hodgkin's disease. Int J STD AIDS, Vol.11,
No.8, pp. 492-494.
Powles, T.; Robinson, D.; Stebbing, J.; Shamash, J.; Nelson, M.; Gazzard, B.; Mandelia, S.;
Moller, H. & Bower, M. (2009). Highly active antiretroviral therapy and the
incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol,
Vol.27, No.6, pp. 884-890, 1527-7755
Prehn, R.T. (1972). The immune reaction as a stimulator of tumor growth. Science, Vol.176,
No.31, pp. 170-171, 0036-8075
Puthier, D.; Derenne, S.; Barille, S.; Moreau, P.; Harousseau, J.L.; Bataille, R. & Amiot, M.
(1999). Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells. Br J
Haematol, Vol.107, No.2, pp. 392-395, 0007-1048
Quezada, S.A.; Simpson, T.R.; Peggs, K.S.; Merghoub, T.; Vider, J.; Fan, X.; Blasberg, R.;
Yagita, H.; Muranski, P.; Antony, P.A.; Restifo, N.P. & Allison, J.P. (2010). Tumor-
reactive CD4(+) T cells develop cytotoxic activity and eradicate large established
melanoma after transfer into lymphopenic hosts. J Exp Med, Vol.207, No.3, pp. 637-
650, 1540-9538
Raphael, M.; Said, J.; Borish, B. & al., e. (2008). Lymphomas associated with HIV infection.
In: World Health Organization Classification of Tumours, Pathology and Genetics of
Tumours of Haematopoietic and Lymphoid Tissues. , Swerdlow SH C.E., Harris NL, et
al. (eds) (eds), 340-342. IARC Press Lyon
Rassidakis, G.Z.; Medeiros, L.J.; McDonnell, T.J.; Viviani, S.; Bonfante, V.; Nadali, G.;
Vassilakopoulos, T.P.; Giardini, R.; Chilosi, M.; Kittas, C.; Gianni, A.M.;
Bonadonna, G.; Pizzolo, G.; Pangalis, G.A.; Cabanillas, F. & Sarris, A.H. (2002a).
BAX expression in Hodgkin and Reed-Sternberg cells of Hodgkin's disease:
correlation with clinical outcome. Clin Cancer Res, Vol.8, No.2, pp. 488-493, 1078-
0432
Rassidakis, G.Z.; Medeiros, L.J.; Vassilakopoulos, T.P.; Viviani, S.; Bonfante, V.; Nadali, G.;
Herling, M.; Angelopoulou, M.K.; Giardini, R.; Chilosi, M.; Kittas, C.; McDonnell,
T.J.; Bonadonna, G.; Gianni, A.M.; Pizzolo, G.; Pangalis, G.A.; Cabanillas, F. &
Sarris, A.H. (2002b). BCL-2 expression in Hodgkin and Reed-Sternberg cells of
classical Hodgkin disease predicts a poorer prognosis in patients treated with
ABVD or equivalent regimens. Blood, Vol.100, No.12, pp. 3935-3941, 0006-4971
Rathore, B. & Kadin, M.E. (2010). Hodgkin's lymphoma therapy: past, present, and future.
Expert Opin Pharmacother, Vol.11, No.17, pp. 2891-2906, 1744-7666
Rautert, R.; Schinkothe, T.; Franklin, J.; Weihrauch, M.; Boll, B.; Pogge, E.; Bredenfeld, H.;
Engert, A.; Diehl, V. & Re, D. (2008). Elevated pretreatment interleukin-10 serum
level is an International Prognostic Score (IPS)-independent risk factor for early
treatment failure in advanced stage Hodgkin lymphoma. Leuk Lymphoma, Vol.49,
No.11, pp. 2091-2098, 1029-2403
Rehwald, U.; Schulz, H.; Reiser, M.; Sieber, M.; Staak, J.O.; Morschlauser, F.; Driessen, C.;
Rudiger, T.; Muller-Hermelin, K.; Diehl, V.; Engert, A. (2003). Treatment of
relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is
Hodgkin's Lymphoma
104
effective and well tolerated: results of a phase 2 trial of the German Hodgkin
lymphoma study group. Blood , Vol 101, No 2, pp 420-424, 0006-4971
Ren, F.; Zhan, X.; Martens, G.; Lee, J.; Center, D.; Hanson, S.K. & Kornfeld, H. (2005). Pro-IL-
16 regulation in activated murine CD4+ lymphocytes. J Immunol, Vol.174, No.5, pp.
2738-2745, 0022-1767
Renne, C.; Martin-Subero, J.I.; Eickernjager, M.; Hansmann, M.L.; Kuppers, R.; Siebert, R. &
Brauninger, A. (2006). Aberrant expression of ID2, a suppressor of B-cell-specific
gene expression, in Hodgkin's lymphoma. Am J Pathol, Vol.169, No.2, pp. 655-664,
0002-9440
Rickinson, A. & Kieff, E. (2001). Epstein-Barr virus. In: In Fields Virology, Knipe DM H.P.e.
(eds),2575-2627. Lippincott Williams & Wilkins Philadelphia
Rohr, J.C.; Wagner, H.J.; Lauten, M.; Wacker, H.H.; Juttner, E.; Hanke, C.; Pohl, M. &
Niemeyer, C.M. (2008). Differentiation of EBV-induced post-transplant Hodgkin
lymphoma from Hodgkin-like post-transplant lymphoproliferative disease. Pediatr
Transplant, Vol.12, No.4, pp. 426-431, 1399-3046
Roskrow, M.A.; Suzuki, N.; Gan, Y.; Sixbey, J.W.; Ng, C.Y.; Kimbrough, S.; Hudson, M.;
Brenner, M.K.; Heslop, H.E. & Rooney, C.M. (1998). Epstein-Barr virus (EBV)-
specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive
relapsed Hodgkin's disease. Blood, Vol.91, No.8, pp. 2925-2934, 0006-4971
Rudant, J.; Orsi, L.; Monnereau, A.; Patte, C.; Pacquement, H.; Landman-Parker, J.; Bergeron,
C.; Robert, A.; Michel, G.; Lambilliotte, A.; Aladjidi, N.; Gandemer, V.; Lutz, P.;
Margueritte, G.; Plantaz, D.; Mechinaud, F.; Hemon, D. & Clavel, J. (2010).
Childhood hodgkin's lymphoma, non-Hodgkin's lymphoma and factors related to
the immune system: the Escale study (SFCE). Int J Cancer, pp. 1097-0215, 0020-7136
Sabattini, E.; Gerdes, J.; Gherlinzoni, F.; Poggi, S.; Zucchini, L.; Melilli, G.; Grigioni, F.; Del
Vecchio, M.T.; Leoncini, L. & Falini, B. (1993). Comparison between the monoclonal
antibodies Ki-67 and PC10 in 125 malignant lymphomas. J Pathol, Vol.169, No.4, pp.
397-403, 0022-3417
Sanchez-Aguilera, A.; Montalban, C.; de la Cueva, P.; Sanchez-Verde, L.; Morente, M.M.;
Garcia-Cosio, M.; Garcia-Larana, J.; Bellas, C.; Provencio, M.; Romagosa, V.; de
Sevilla, A.F.; Menarguez, J.; Sabin, P.; Mestre, M.J.; Mendez, M.; Fresno, M.F.;
Nicolas, C.; Piris, M.A. & Garcia, J.F. (2006). Tumor microenvironment and mitotic
checkpoint are key factors in the outcome of classic Hodgkin lymphoma. Blood,
Vol.108, No.2, pp. 662-668, 0006-4971
Sanchez-Beato, M.; Piris, M.A.; Martinez-Montero, J.C.; Garcia, J.F.; Villuendas, R.; Garcia,
F.J.; Orradre, J.L. & Martinez, P. (1996). MDM2 and p21WAF1/CIP1, wild-type
p53-induced proteins, are regularly expressed by Sternberg-Reed cells in Hodgkin's
disease. J Pathol, Vol.180, No.1, pp. 58-64, 0022-3417
Sanchez-Beato, M.; Sanchez-Aguilera, A. & Piris, M.A. (2003). Cell cycle deregulation in B-
cell lymphomas. Blood, Vol.101, No.4, pp. 1220-1235, 0006-4971
Sarris, A.H.; Kliche, K.O.; Pethambaram, P.; Preti, A.; Tucker, S.; Jackow, C.; Messina, O.;
Pugh, W.; Hagemeister, F.B.; McLaughlin, P.; Rodriguez, M.A.; Romaguera, J.;
Fritsche, H.; Witzig, T.; Duvic, M.; Andreeff, M. & Cabanillas, F. (1999). Interleukin-
10 levels are often elevated in serum of adults with Hodgkin's disease and are
associated with inferior failure-free survival. Ann Oncol, Vol.10, No.4, pp. 433-440,
0923-7534
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
105
Schmitz, R.; Hansmann, M.L.; Bohle, V.; Martin-Subero, J.I.; Hartmann, S.; Mechtersheimer,
G.; Klapper, W.; Vater, I.; Giefing, M.; Gesk, S.; Stanelle, J.; Siebert, R. & Kuppers, R.
(2009). TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and
primary mediastinal B cell lymphoma. J Exp Med, Vol.206, No.5, pp. 981-989, 1540-
9538
Schnell, R.; Dietlein, M.; Staak, J.O.; Borchmann, P.; Schomaecker, K.; Fischer, T.; Eschner,
W.; Hansen, H.; Morschhauser, F.; Schicha, H.; Diehl, V.; Raubitschek, A. & Engert,
A. (2005). Treatment of refractory Hodgkin's lymphoma patients with an iodine-
131-labeled murine anti-CD30 monoclonal antibody. J Clin Oncol, Vol.23, No.21, pp.
4669-4678, 0732-183X
Schulz, H.; Rehwald, U.; Morschhauser, F.; Elter, T.; Driessen, C.; Rudiger, T.; Borchmann,
P.; Schnell, R.; Diehl, V.; Engert, A. & Reiser, M. (2008). Rituximab in relapsed
lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial
by the German Hodgkin Lymphoma Study Group (GHSG). Blood, Vol.111, No.1,
pp. 109-111, 0006-4971
Schwering, I.; Brauninger, A.; Klein, U.; Jungnickel, B.; Tinguely, M.; Diehl, V.; Hansmann,
M.L.; Dalla-Favera, R.; Rajewsky, K. & Kuppers, R. (2003). Loss of the B-lineage-
specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin
lymphoma. Blood, Vol.101, No.4, pp. 1505-1512, 0006-4971
Seitz, V.; Hummel, M.; Marafioti, T.; Anagnostopoulos, I.; Assaf, C. & Stein, H. (2000).
Detection of clonal T-cell receptor gamma-chain gene rearrangements in Reed-
Sternberg cells of classic Hodgkin disease. Blood, Vol.95, No.10, pp. 3020-3024, 0006-
4971
Shaffer, A.L.; Yu, X.; He, Y.; Boldrick, J.; Chan, E.P. & Staudt, L.M. (2000). BCL-6 represses
genes that function in lymphocyte differentiation, inflammation, and cell cycle
control. Immunity, Vol.13, No.2, pp. 199-212, 1074-7613
Shimizu, J.; Yamazaki, S.; Takahashi, T.; Ishida, Y. & Sakaguchi, S. (2002). Stimulation of
CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-
tolerance. Nat Immunol, Vol.3, No.2, pp. 135-142, 1529-2908
Skinnider, B.F.; Elia, A.J.; Gascoyne, R.D.; Patterson, B.; Trumper, L.; Kapp, U. & Mak, T.W.
(2002). Signal transducer and activator of transcription 6 is frequently activated in
Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood, Vol.99, No.2, pp.
618-626, 0006-4971
Skinnider, B.F. & Mak, T.W. (2002). The role of cytokines in classical Hodgkin lymphoma.
Blood, Vol.99, No.12, pp. 4283-4297, 0006-4971
Slovak, M.L.; Bedell, V.; Hsu, Y.H.; Estrine, D.B.; Nowak, N.J.; Delioukina, M.L.; Weiss, L.M.;
Smith, D.D. & Forman, S.J. (2011). Molecular karyotypes of Hodgkin and Reed-
Sternberg cells at disease onset reveal distinct copy number alterations in
chemosensitive versus refractory Hodgkin lymphoma. Clin Cancer Res, Vol.17,
No.10, pp. 3443-3454, 1078-0432
Smith, E.M.; Akerblad, P.; Kadesch, T.; Axelson, H. & Sigvardsson, M. (2005). Inhibition of
EBF function by active Notch signaling reveals a novel regulatory pathway in early
B-cell development. Blood, Vol.106, No.6, pp. 1995-2001, 0006-4971
Smolewski, P.; Robak, T.; Krykowski, E.; Blasinska-Morawiec, M.; Niewiadomska, H.;
Pluzanska, A.; Chmielowska, E. & Zambrano, O. (2000). Prognostic factors in
Hodgkin's Lymphoma
106
Hodgkin's disease: multivariate analysis of 327 patients from a single institution.
Clin Cancer Res, Vol.6, No.3, pp. 1150-1160, 1078-0432
Smyth, M.J.; Hayakawa, Y.; Takeda, K. & Yagita, H. (2002). New aspects of natural-killer-cell
surveillance and therapy of cancer. Nat Rev Cancer, Vol.2, No.11, pp. 850-861, 1474-
175X
Song, L.; Li, Y.; Sun, Y. & Shen, B. (2002). Mcl-1 mediates cytokine deprivation induced
apoptosis of human myeloma cell line XG-7. Chin Med J (Engl), Vol.115, No.8, pp.
1241-1243, 0366-6999
Specht, L. & Hasenclever, D. (1999). Prognostic factors of Hodgkin´s disease. In: Hodgkin´s
disease. , Mauch PM A.J., Diehl V, Hoppe RT, Weiss LM (eds). (eds),295-325.
Lippincott Williams & Wilkins Philadelphia:295-325
Staudt, L.M. (2000). The molecular and cellular origins of Hodgkin's disease. J Exp Med,
Vol.191, No.2, pp. 207-212, 0022-1007
Steidl, C.; Connors, J.M. & Gascoyne, R.D. (2011a). Molecular pathogenesis of Hodgkin's
lymphoma: increasing evidence of the importance of the microenvironment. J Clin
Oncol, Vol.29, No.14, pp. 1812-1826, 1527-7755
Steidl, C.; Lee, T.; Shah, S.P.; Farinha, P.; Han, G.; Nayar, T.; Delaney, A.; Jones, S.J.; Iqbal, J.;
Weisenburger, D.D.; Bast, M.A.; Rosenwald, A.; Muller-Hermelink, H.K.; Rimsza,
L.M.; Campo, E.; Delabie, J.; Braziel, R.M.; Cook, J.R.; Tubbs, R.R.; Jaffe, E.S.; Lenz,
G.; Connors, J.M.; Staudt, L.M.; Chan, W.C. & Gascoyne, R.D. (2010). Tumor-
associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J
Med, Vol.362, No.10, pp. 875-885, 1533-4406
Steidl, C.; Shah, S.P.; Woolcock, B.W.; Rui, L.; Kawahara, M.; Farinha, P.; Johnson, N.A.;
Zhao, Y.; Telenius, A.; Neriah, S.B.; McPherson, A.; Meissner, B.; Okoye, U.C.;
Diepstra, A.; van den Berg, A.; Sun, M.; Leung, G.; Jones, S.J.; Connors, J.M.;
Huntsman, D.G.; Savage, K.J.; Rimsza, L.M.; Horsman, D.E.; Staudt, L.M.; Steidl,
U.; Marra, M.A. & Gascoyne, R.D. (2011b). MHC class II transactivator CIITA is a
recurrent gene fusion partner in lymphoid cancers. Nature, Vol.471, No.7338, pp.
377-381, 1476-4687
Stein, H.; Delsol, G. & Pileri, S. (2008a). Classical Hodgkin lymphoma, introduction. In:
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. , Swerdlow
SH C.E., Harris NL, et al. (eds) (eds),326-329. IARC Lyon
Stein, H.; Marafioti, T.; Foss, H.D.; Laumen, H.; Hummel, M.; Anagnostopoulos, I.; Wirth, T.;
Demel, G. & Falini, B. (2001). Down-regulation of BOB.1/OBF.1 and Oct2 in
classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease
correlates with immunoglobulin transcription. Blood, Vol.97, No.2, pp. 496-501,
0006-4971
Stein, R.; Von Wasielewski; Poppema, S.; MacLennan, K. & Guenova, M. (2008b). Nodular
sclerosis classical Hodgkin lymphoma. In: WHO Classification of Tumors of
Haematopoietic and Lymphoid Tissues Swerdlow S., Campo E., Harris N., Jaffe E.,
Pileri S., Stein H., al. e. (eds),330, IARC, Lyon, France
Stupp, R. & Ruegg, C. (2007). Integrin inhibitors reaching the clinic. J Clin Oncol, Vol.25,
No.13, pp. 1637-1638, 1527-7755
Sup, S.J.; Alemany, C.A.; Pohlman, B.; Elson, P.; Malhi, S.; Thakkar, S.; Steinle, R. & Hsi, E.D.
(2005). Expression of bcl-2 in classical Hodgkin's lymphoma: an independent
predictor of poor outcome. J Clin Oncol, Vol.23, No.16, pp. 3773-3779, 0732-183X
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
107
Suri-Payer, E.; Amar, A.Z.; Thornton, A.M. & Shevach, E.M. (1998). CD4+CD25+ T cells
inhibit both the induction and effector function of autoreactive T cells and
represent a unique lineage of immunoregulatory cells. J Immunol, Vol.160, No.3, pp.
1212-1218,
Sutmuller, R.P.; van Duivenvoorde, L.M.; van Elsas, A.; Schumacher, T.N.; Wildenberg,
M.E.; Allison, J.P.; Toes, R.E.; Offringa, R. & Melief, C.J. (2001). Synergism of
cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+)
regulatory T cells in antitumor therapy reveals alternative pathways for
suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med, Vol.194,
No.6, pp. 823-832
Swerdlow, S.; Campo, E. & Harris, N. (2008a). Pathology and Genetics of Tumours of
Haematopoietic and Lymphoid Tissues. In: World Health Organization Classification
of Tumours, Swerdlow SH C.E., Harris NL (eds). IARC Press Lyon
Swerdlow, S.; Campo, E.; Harris. NL; Jaffe, E.; Pileri, S.; Stein, H.; Thiele, J. & Vardiman, J.
(2008b). WHO classification of tumours of haematopoietic and lymphoid tissues. IARC
Press Lyon, France
Swerdlow, S.; Webber, S.; A., C. & Ferry, J. (2008c). Post-transplant lymphoproliferative
disorders. In: World Health Organization Classification of Tumours, Pathology and
Genetics of Tumours of Haematopoietic and Lymphoid Tissues. , Swerdlow SH C.E.,
Harris NL, et al. (eds) (eds),343-349. IARC Press Lyon
Takahashi, T.; Tagami, T.; Yamazaki, S.; Uede, T.; Shimizu, J.; Sakaguchi, N.; Mak, T.W. &
Sakaguchi, S. (2000). Immunologic self-tolerance maintained by CD25(+)CD4(+)
regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated
antigen 4. J Exp Med, Vol.192, No.2, pp. 303-310, 0022-1007
Tang, T.T.; Dowbenko, D.; Jackson, A.; Toney, L.; Lewin, D.A.; Dent, A.L. & Lasky, L.A.
(2002). The forkhead transcription factor AFX activates apoptosis by induction of
the BCL-6 transcriptional repressor. J Biol Chem, Vol.277, No.16, pp. 14255-14265,
0021-9258
Tazzari, P.L.; Bolognesi, A.; de Totero, D.; Falini, B.; Lemoli, R.M.; Soria, M.R.; Pileri, S.;
Gobbi, M.; Stein, H.; Flenghi, L. & et al. (1992). Ber-H2 (anti-CD30)-saporin
immunotoxin: a new tool for the treatment of Hodgkin's disease and CD30+
lymphoma: in vitro evaluation. Br J Haematol, Vol.81, No.2, pp. 203-211, 0007-1048
Tedoldi, S.; Mottok, A.; Ying, J.; Paterson, J.C.; Cui, Y.; Facchetti, F.; van Krieken, J.H.;
Ponzoni, M.; Ozkal, S.; Masir, N.; Natkunam, Y.; Pileri, S.; Hansmann, M.L.; Mason,
D.; Tao, Q. & Marafioti, T. (2007). Selective loss of B-cell phenotype in lymphocyte
predominant Hodgkin lymphoma. J Pathol, Vol.213, No.4, pp. 429-440, 0022-3417
Teichmann, M.; Meyer, B.; Beck, A. & Niedobitek, G. (2005). Expression of the interferon-
inducible chemokine IP-10 (CXCL10), a chemokine with proposed anti-neoplastic
functions, in Hodgkin lymphoma and nasopharyngeal carcinoma. J Pathol, Vol.206,
No.1, pp. 68-75, 0022-3417
ten Berge, R.L.; Oudejans, J.J.; Dukers, D.F.; Meijer, J.W.; Ossenkoppele, G.J. & Meijer, C.J.
(2001). Percentage of activated cytotoxic T-lymphocytes in anaplastic large cell
lymphoma and Hodgkin's disease: an independent biological prognostic marker.
Leukemia, Vol.15, No.3, pp. 458-464
Hodgkin's Lymphoma
108
Teramoto, N.; Pokrovskaja, K.; Szekely, L.; Polack, A.; Yoshino, T.; Akagi, T. & Klein, G.
(1999). Expression of cyclin D2 and D3 in lymphoid lesions. Int J Cancer, Vol.81,
No.4, pp. 543-550, 0020-7136
Tesniere, A.; Apetoh, L.; Ghiringhelli, F.; Joza, N.; Panaretakis, T.; Kepp, O.; Schlemmer, F.;
Zitvogel, L. & Kroemer, G. (2008). Immunogenic cancer cell death: a key-lock
paradigm. Curr Opin Immunol, Vol.20, No.5, pp. 504-511, 0952-7915
Thomas, R.K.; Re, D.; Wolf, J. & Diehl, V. (2004). Part I: Hodgkin's lymphoma--molecular
biology of Hodgkin and Reed-Sternberg cells. Lancet Oncol, Vol.5, No.1, pp. 11-18,
1470-2045
Thome, M. & Tschopp, J. (2001). Regulation of lymphocyte proliferation and death by FLIP.
Nat Rev Immunol, Vol.1, No.1, pp. 50-58, 1474-1733
Tirelli, U.; Errante, D.; Dolcetti, R.; Gloghini, A.; Serraino, D.; Vaccher, E.; Franceschi, S.;
Boiocchi, M. & Carbone, A. (1995). Hodgkin's disease and human
immunodeficiency virus infection: clinicopathologic and virologic features of 114
patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol,
Vol.13, No.7, pp. 1758-1767, 0732-183X
Tlsty, T.D. & Coussens, L.M. (2006). Tumor stroma and regulation of cancer development.
Annu Rev Pathol, Vol.1, pp. 119-150, 1553-4006
Tsavaris, N.; Kosmas, C.; Vadiaka, M.; Kanelopoulos, P. & Boulamatsis, D. (2002). Immune
changes in patients with advanced breast cancer undergoing chemotherapy with
taxanes. Br J Cancer, Vol.87, No.1, pp. 21-27, 0007-0920
Tzankov, A.; Krugmann, J.; Fend, F.; Fischhofer, M.; Greil, R. & Dirnhofer, S. (2003a).
Prognostic significance of CD20 expression in classical Hodgkin lymphoma: a
clinicopathological study of 119 cases. Clin Cancer Res, Vol.9, No.4, pp. 1381-1386,
1078-0432
Tzankov, A.; Zimpfer, A.; Lugli, A.; Krugmann, J.; Went, P.; Schraml, P.; Maurer, R.; Ascani,
S.; Pileri, S.; Geley, S. & Dirnhofer, S. (2003b). High-throughput tissue microarray
analysis of G1-cyclin alterations in classical Hodgkin's lymphoma indicates
overexpression of cyclin E1. J Pathol, Vol.199, No.2, pp. 201-207
Tzankov, A.; Zimpfer, A.; Pehrs, A.C.; Lugli, A.; Went, P.; Maurer, R.; Pileri, S. & Dirnhofer,
S. (2003c). Expression of B-cell markers in classical hodgkin lymphoma: a tissue
microarray analysis of 330 cases. Mod Pathol, Vol.16, No.11, pp. 1141-1147, 0893-
3952
Tzardi, M.; Kouvidou, C.; Panayiotides, I.; Koutsoubi, K.; Stefanaki, K.; Giannikaki, E.;
Darivianaki, K.; Zois, M.; Eliopoulos, G.; Kakolyris, S.; Delides, G.; Rontogianni, D.
& Kanavaros, P. (1996). Expression of p53 and mdm-2 proteins in Hodgkin's
Disease. Absence of correlation with the presence of Epstein-Barr virus. Anticancer
Res, Vol.16, No.5A, pp. 2813-2819, 0250-7005
Ushmorov, A.; Leithauser, F.; Sakk, O.; Weinhausel, A.; Popov, S.W.; Moller, P. & Wirth, T.
(2006). Epigenetic processes play a major role in B-cell-specific gene silencing in
classical Hodgkin lymphoma. Blood, Vol.107, No.6, pp. 2493-2500, 0006-4971
Ushmorov, A.; Ritz, O.; Hummel, M.; Leithauser, F.; Moller, P.; Stein, H. & Wirth, T. (2004).
Epigenetic silencing of the immunoglobulin heavy-chain gene in classical Hodgkin
lymphoma-derived cell lines contributes to the loss of immunoglobulin expression.
Blood, Vol.104, No.10, pp. 3326-3334, 0006-4971
Hodgkin’s Lymphoma: From Tumor Microenvironment
to Immunotherapeutic Approach - Body’s Own Power Protection Challenges
109
Vaccher, E.; Spina, M.; Talamini, R.; Zanetti, M.; di Gennaro, G.; Nasti, G.; Tavio, M.;
Bernardi, D.; Simonelli, C. & Tirelli, U. (2003). Improvement of systemic human
immunodeficiency virus-related non-Hodgkin lymphoma outcome in the era of
highly active antiretroviral therapy. Clin Infect Dis, Vol.37, No.11, pp. 1556-1564,
1537-6591
van den Berg, A.; Visser, L. & Poppema, S. (1999). High expression of the CC chemokine
TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell
infiltratein Hodgkin's lymphoma. Am J Pathol, Vol.154, No.6, pp. 1685-1691, 0002-
9440
Vassilakopoulos, T.P.; Nadali, G.; Angelopoulou, M.K.; Siakantaris, M.P.; Dimopoulou,
M.N.; Kontopidou, F.N.; Rassidakis, G.Z.; Doussis-Anagnostopoulou, I.A.;
Hatzioannou, M.; Vaiopoulos, G.; Kittas, C.; Sarris, A.H.; Pizzolo, G. & Pangalis,
G.A. (2001). Serum interleukin-10 levels are an independent prognostic factor for
patients with Hodgkin's lymphoma. Haematologica, Vol.86, No.3, pp. 274-281, 0390-
6078
Viviani, S.; Notti, P.; Bonfante, V.; Verderio, P.; Valagussa, P. & Bonadonna, G. (2000).
Elevated pretreatment serum levels of Il-10 are associated with a poor prognosis in
Hodgkin's disease, the milan cancer institute experience. Med Oncol, Vol.17, No.1,
pp. 59-63, 1357-0560
Wagner, E.F.; Hleb, M.; Hanna, N. & Sharma, S. (1998). A pivotal role of cyclin D3 and
cyclin-dependent kinase inhibitor p27 in the regulation of IL-2-, IL-4-, or IL-10-
mediated human B cell proliferation. J Immunol, Vol.161, No.3, pp. 1123-1131, 0022-
1767
Watanabe, K.; Yamashita, Y.; Nakayama, A.; Hasegawa, Y.; Kojima, H.; Nagasawa, T. &
Mori, N. (2000). Varied B-cell immunophenotypes of Hodgkin/Reed-Sternberg
cells in classic Hodgkin's disease. Histopathology, Vol.36, No.4, pp. 353-361, 0309-
0167
Wei, W.Z.; Morris, G.P. & Kong, Y.C. (2004). Anti-tumor immunity and autoimmunity: a
balancing act of regulatory T cells. Cancer Immunol Immunother, Vol.53, No.2, pp. 73-
78
Weihrauch, M.R.; Manzke, O.; Beyer, M.; Haverkamp, H.; Diehl, V.; Bohlen, H.; Wolf, J. &
Schultze, J.L. (2005). Elevated serum levels of CC thymus and activation-related
chemokine (TARC) in primary Hodgkin's disease: potential for a prognostic factor.
Cancer Res, Vol.65, No.13, pp. 5516-5519, 0008-5472
Weniger, M.A.; Melzner, I.; Menz, C.K.; Wegener, S.; Bucur, A.J.; Dorsch, K.; Mattfeldt, T.;
Barth, T.F. & Moller, P. (2006). Mutations of the tumor suppressor gene SOCS-1 in
classical Hodgkin lymphoma are frequent and associated with nuclear phospho-
STAT5 accumulation. Oncogene, Vol.25, No.18, pp. 2679-2684, 0950-9232
Willenbrock, K.; Roers, A.; Blohbaum, B.; Rajewsky, K. & Hansmann, M.L. (2000). CD8(+) T
cells in Hodgkin's disease tumor tissue are a polyclonal population with limited
clonal expansion but little evidence of selection by antigen. Am J Pathol, Vol.157,
No.1, pp. 171-175
Wolf, A.M.; Wolf, D.; Steurer, M.; Gastl, G.; Gunsilius, E. & Grubeck-Loebenstein, B. (2003).
Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer
Res, Vol.9, No.2, pp. 606-612, 1078-0432
Hodgkin's Lymphoma
110
Wood, K.M.; Roff, M. & Hay, R.T. (1998). Defective IkappaBalpha in Hodgkin cell lines with
constitutively active NF-kappaB. Oncogene, Vol.16, No.16, pp. 2131-2139, 0950-9232
Xicoy, B.; Ribera, J.M.; Miralles, P.; Berenguer, J.; Rubio, R.; Mahillo, B.; Valencia, M.E.;
Abella, E.; Lopez-Guillermo, A.; Sureda, A.; Morgades, M.; Navarro, J.T. & Esteban,
H. (2007). Results of treatment with doxorubicin, bleomycin, vinblastine and
dacarbazine and highly active antiretroviral therapy in advanced stage, human
immunodeficiency virus-related Hodgkin's lymphoma. Haematologica, Vol.92, No.2,
pp. 191-198, 1592-8721
Yamamoto, R.; Nishikori, M.; Kitawaki, T.; Sakai, T.; Hishizawa, M.; Tashima, M.; Kondo, T.;
Ohmori, K.; Kurata, M.; Hayashi, T. & Uchiyama, T. (2008). PD-1-PD-1 ligand
interaction contributes to immunosuppressive microenvironment of Hodgkin
lymphoma. Blood, Vol.111, No.6, pp. 3220-3224, 0006-4971
Younes, A. (2009). Novel treatment strategies for patients with relapsed classical Hodgkin
lymphoma. Hematology Am Soc Hematol Educ Program, pp. 507-519, 1520-4383
Younes, A.; Bartlett, N.L.; Leonard, J.P.; Kennedy, D.A.; Lynch, C.M.; Sievers, E.L. & Forero-
Torres, A. (2010). Brentuximab vedotin (SGN-35) for relapsed CD30-positive
lymphomas. N Engl J Med, Vol.363, No.19, pp. 1812-1821, 1533-4406
Young, L.S. & Rickinson, A.B. (2004). Epstein-Barr virus: 40 years on. Nat Rev Cancer, Vol.4,
No.10, pp. 757-768, 1474-175X
Zheng, B.; Fiumara, P.; Li, Y.V.; Georgakis, G.; Snell, V.; Younes, M.; Vauthey, J.N.; Carbone,
A. & Younes, A. (2003). MEK/ERK pathway is aberrantly active in Hodgkin
disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell
proliferation and survival. Blood, Vol.102, No.3, pp. 1019-1027, 0006-4971
Zhu, J. & Paul, W.E. (2008). CD4 T cells: fates, functions, and faults. Blood, Vol.112, No.5, pp.
1557-1569, 1528-0020
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Chapter
Full-text available
The complex of humoral factors and immune cells comprises two interleaved systems, innate and acquired. Immune cells scan the occurrence of any molecule that it considers to be nonself. Transformed cells acquire antigenicity that is recognized as nonself. A specific immune response is generated that results in the proliferation of antigen-specific lymphocytes. Immunity is acquired when antibodies and T-cell receptors are expressed and up-regulated through the formation and release of lymphokines, chemokines, and cytokines. Both innate and acquired immune systems interact to initiate antigenic responses against carcinomas. A new approach to the treatment of cancer has been immunotherapy, which aims to up-regulate the immune system in order that it may better control carcinogenesis. Currently, several forms of immunotherapy that use natural biological substances to activate the immune system are being explored therapeutically. The various forms of immunotherapy fall into three main categories: monoclonal antibodies, immune response modifiers, and vaccines. While these modalities have individually shown some promise, it is likely that the best strategy to combat cancer may require multiple immunotherapeutic strategies in order to demonstrate benefit in different patient populations. It may be that the best results are obtained with vaccines in combination with a variety of immunotherapy combinations. Another potent strategy may be in combining with more traditional cancer drugs as evidenced from the benefit derived from enhancing the efficacy of chemotherapy with cytokines. Through such concerted efforts, a durable, therapeutic antitumour immune response may be achieved and maintained over the course of a patient's lifespan.
Article
Background: Classical Hodgkin's disease (HD) and B-cell non-Hodgkin lymphoma (NHL) occasionally occur in the same patient. Such composite lymphomas represent interesting models to study the pathogenesis of B-cell lymphomas and the relationship between HD and B-cell NHL. Materials and Methods: We analyzed two composite lymphomas (a combination of classical HD with follicular lymphoma [FL] and a combination of classical HD with B-cell chronic lymphocytic leukemia [B-CLL]) by micromanipulation of single cells from tissue sections and amplification of immunoglobulin V region genes for the clonal relationship of the tumor cells. Results: In both cases, clonally related variable (V) genes with both shared as well as distinct somatic mutations were obtained from the two lymphomas, showing that in each of the cases the distinct tumor cells were members of a common germinal center (GC) B-cell clone. FL cells from two different lymph nodes of patient I showed a similar mutation pattern, suggesting that infiltration of these lymph nodes by tumor cells was not restricted to a particular FL cell or subclone. In the FL, a single cell was identified with a mutation signature indicating that premalignant cells can persist in the tissue. Conclusions: The cases presented here further underline the close relationship between HD and B-cell NHL and the role of the GC in lymphomagenesis. Whereas the latter was already suggested for FL and HD, the present study indicates that also in the B-CLL subset characterized by mutated Ig genes, important steps in malignant transformation happen in the GC, and that HRS cells can derive from CDS-positive B cells.
Article
1. 1. Schmitz, 2. et al . 2009. J. Exp. Med. doi: 10.1084/jem.20090528 [OpenUrl][1][Abstract/FREE Full Text][2] [1]: {openurl}?query=rft_id%253Dinfo%253Adoi%252F10.1084%252Fjem.20090528%26rft_id%253Dinfo%253Apmid%252F19380639%26rft.genre%253Darticle%26rft_val_fmt%