Immunobiology of Merkel cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer.
ABSTRACT Merkel cell carcinoma (MCC) is an aggressive skin malignancy with a high mortality rate and an increasing incidence. The recent discovery of Merkel cell polyomavirus has revolutionized our understanding of MCC pathogenesis. Viral oncoproteins appear to play a critical role in tumor progression and are expressed in the majority of MCC tumors. Virus-specific humoral and cellular immune responses are detectable in MCC patients and are linked to the natural history of the disease. Despite persistent expression of immunogenic viral proteins, however, MCC tumors are able to evade the immune system. Understanding of the mechanisms of immune evasion employed by MCC tumors is rapidly increasing and offers opportunities for development of rational immune therapies to improve patient outcomes. Here we review recent discoveries in MCC with a special focus on the pathogenic role of Merkel cell polyomavirus and the immunobiology of this virus-associated disease.
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ABSTRACT: The relatively high incidence of Merkel cell carcinoma (MCC) in Queensland provides a valuable opportunity to examine links with other cancers. A retrospective cohort study was performed using data from the Queensland Cancer Registry. Standardised incidence ratios (SIRs) were used to approximate the relative risk of being diagnosed with another primary cancer either following or prior to MCC. Patients with an eligible first primary MCC (n=787) had more than double the expected number of subsequent primary cancers (SIR=2.19, 95% CI=1.84-2.60; P<0.001). Conversely, people who were initially diagnosed with cancers other than MCC were about two and a half times more likely to have a subsequent primary MCC (n=244) compared to the general population (SIR=2.69, 95% CI=2.36-3.05; P<0.001). Significantly increased bi-directional relative risks were found for melanoma, lip cancer, head and neck cancer, lung cancer, myelodysplastic diseases and cancer with unknown primary site. In addition, risks were elevated for female breast cancer and kidney cancer following a first primary MCC, and for subsequent MCCs following first primary colorectal cancer, prostate cancer, non-Hodgkin lymphoma or lymphoid leukaemia. These results suggest that several shared pathways are likely for MCC and other cancers, including immunosuppression, ultraviolet radiation and genetics.Journal of Investigative Dermatology accepted article preview online, 03 July 2014; doi:10.1038/jid.2014.266.Journal of Investigative Dermatology 07/2014; · 6.37 Impact Factor
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ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Immunosuppression is associated with increased incidence of MCC.Journal of the American Academy of Dermatology 06/2014; · 5.00 Impact Factor
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ABSTRACT: Human oncogenic viruses include Epstein-Barr virus, hepatitis B virus, hepatitis C virus, human papilloma virus, human T-cell lymphotropic virus, Kaposi's associated sarcoma virus, and Merkel cell polyomavirus. It would be expected that during virus-host interaction, the immune system would recognize these pathogens and eliminate them. However, through evolution, these viruses have developed a number of strategies to avoid such an outcome and successfully establish chronic infections. The persistent nature of the infection caused by these viruses is associated with their oncogenic potential. In this article, we will review the latest information on the interaction between oncogenic viruses and the innate immune system of the host. In particular, we will summarize the available knowledge on the recognition by host pattern-recognition receptors of pathogen-associated molecular patterns present in the incoming viral particle or generated during the virus' life cycle. We will also review the data on the recognition of cell-derived danger associated molecular patterns generated during the virus infection that may impact the outcome of the host-pathogen interaction and the development cancer.Frontiers in Immunology 07/2014; 5:353.
MELANOMA (KIM MARGOLIN, SECTION EDITOR)
Immunobiology of Merkel Cell Carcinoma: Implications
for Immunotherapy of a Polyomavirus-Associated Cancer
Shailender Bhatia & Olga Afanasiev & Paul Nghiem
# Springer Science+Business Media, LLC 2011
Abstract Merkel cell carcinoma (MCC) is an aggressive
skin malignancy with a high mortality rate and an
increasing incidence. The recent discovery of Merkel cell
polyomavirus has revolutionized our understanding of
MCC pathogenesis. Viral oncoproteins appear to play a
critical role in tumor progression and are expressed in the
majority of MCC tumors. Virus-specific humoral and
cellular immune responses are detectable in MCC patients
and are linked to the natural history of the disease. Despite
MCC tumors are able to evade the immune system.
Understanding of the mechanisms of immune evasion
employed by MCC tumors is rapidly increasing and offers
opportunities for development ofrationalimmunetherapies to
improve patient outcomes. Here we review recent discoveries
in MCC with a special focus on the pathogenic role of Merkel
cell polyomavirus and the immunobiology of this virus-
Keywords Merkel cell carcinoma.Immunotherapy.
Merkel cell polyomavirus.MCV.MCPyV.Cancer virus.
Viral cancer.Immune evasion.Immune escape.MHC.
Tumor immunology.Tumor infiltrating lymphocytes.
TILs.Viral oncoproteins.T-antigen.Immune suppression
Merkel cell carcinoma (MCC) is an aggressive neuroendo-
crine skin cancer with a disease-associated mortality three
[1•]. MCC is an uncommon cancer with an estimated 1,600
cases/year in the US [2, 3]. The reported incidence has more
than tripled over the past 20 years [3, 4], and the health
impact of MCC is growing rapidly with the proportional
increase in the aging population [2, 3]. This increasing
incidence is in part due to improved detection following
availability of a specific immunohistochemical marker,
cytokeratin-20 , but is also likely due to the higher
prevalence of known risk factors for MCC: T-cell immune
suppression and Caucasians over 50 years of age with
extensive prior sun exposure . MCC now kills more
patients than cutaneous T-cell lymphoma and a similar
number as chronic myelogenous leukemia, both well-
known and frequently studied cancers [2, 7, 8].
MCC is an aggressive cancer with prognosis dependent on
represent the presence of nodal and distant metastases,
respectively. The reported 5-year relative survival for patients
with local, nodal, and metastatic disease is 64%, 39% and
S. Bhatia (*)
Departments of Medicine/Medical Oncology,
University of Washington, Fred Hutchinson Cancer Research
Center, Seattle Cancer Care Alliance,
825 Eastlake Avenue E, G4830, Seattle, WA 98109, USA
Departments of Medicine/Dermatology, Pathology,
University of Washington,
815 Mercer Street,
Seattle, WA 98109, USA
Departments of Medicine/Dermatology, Pathology,
University of Washington, Fred Hutchinson Cancer Research
Center, Seattle Cancer Care Alliance,
815 Mercer Street,
Seattle, WA 98109, USA
Curr Oncol Rep
18%, respectively [1•]. Although surgery and/or radiation
therapy (RT) may be curative for patients with locoregional
MCC without distant metastases, relapses are common and
often incurable. There is no established adjuvant therapy
after definitive management. For patients with distant
metastatic disease, systemic chemotherapy is considered.
The objective response rate (ORR) with platinum-based
chemotherapy regimens is around 60% ; however,
responses are usually short-lived and the impact on survival
is unclear. Also, the chemotherapy regimens are associated
with significant toxicity and may not be suitable for many
MCC patients who usually tend to be older with multiple
comorbidities. There are no established second-line treat-
ments for patients who have progressed on initial systemic
need for novel, biology-driven therapies in this disease.
Fortunately, rapid strides are being made in our
understanding of the biology of MCC that have opened
up new avenues for investigation of rational therapies in
this aggressive disease. We review the recent discoveries in
MCC, with a special focus on the emerging importance of
immune mechanisms in the pathogenesis of this disease.
Link with Immune Suppression Leads to Discovery
of Merkel Cell Polyomavirus
Epidemiologic data suggest a strong link between MCC
and the immune system. Individuals with T-cell dysfunction
(solid organ transplant recipients [10, 11], HIV-infected
patients , or chronic lymphocytic leukemia patients )
are at fivefold to 50-fold increased risk of developing
MCC. MCC tumors sometimes regress following improve-
ment in immune function [13, 14], underscoring the
importance of immune surveillance in the development of
MCC. Additionally, there are several reported cases of
complete spontaneous regression in the MCC literature (a
far greater number than expected for its rarity) that suggest
a sudden recognition by the immune system leading to the
clearance of MCC [15–20]. These epidemiologic data
raised the possibility of an infectious etiology for MCC.
Indeed, the recent discovery of the Merkel cell polyoma-
virus (MCV or MCPyV) has provided the missing link
between MCC and its association with immune suppression
The Merkel cell polyomavirus was discovered in 2008
[21••]. Yuan Chang, Patrick Moore, and their colleagues
created cDNA libraries from MCC tumor mRNA and used
the Digital Transcriptome Subtraction method to identify a
novel transcript with high homology to the African green
monkey lymphotropic polyomavirus (AGM LPyV). The
circular genome of MCPyV (~5,200 base pairs) has an
early gene expression region containing the oncoprotein
tumor (T) antigen locus with large T (LT) and small T (ST)
open reading frames. A late gene region contains the viral
structural proteins that encode capsid proteins. MCpyV was
found to have the highest homology with the murine
polyomavirus subgroup (includes AGM LPyV) and lesser
homology to the known human polyomaviruses (BK or JC
viruses) or to simian virus 40 (SV40). PCR-Southern
hybridization revealed MCPyV sequences to be present in
8 of 10 (80%) MCC tumors, but uncommon in non-MCC
tissues (8%) and normal skin or non-MCC skin tumor
tissues (16%), suggesting strong association between
MCPyV infection and MCC. The monoclonal pattern of
integration of the viral genome into the tumor genome was
suggestive of MCPyV infection and genomic integration
prior to or very early in tumorigenesis. Since the original
description of the virus in 2008, several groups around the
world have independently verified the association between
MCPyV and MCC [22–26•, 27, 28].
Epidemiology of MCPyV Infection
Similar to the other known human polyomaviruses (BK,
JC, KI, and WU viruses) , exposure to MCPyV as
measured by serum antibodies to viral capsid proteins
appears to be widely prevalent among healthy subjects [30–
32]. In one study, the prevalence of MCPyV seropositivity
was 0% in infants, 43% among children aged 2–5 years old,
and increased to 80% among adults older than 50 years
. A similar trend of increasing seroprevalence with age
was seen in another study, suggesting that primary exposure
to MCPyV occurs during childhood . Consistent with
the serologic data, MCPyV DNAwas detected in cutaneous
swabs from clinically healthy subjects with a prevalence of
40%–100% in three independent studies [33–35]; it appears
that the virus is being shed chronically from clinically
normal skin in the form of assembled virions . Besides
the skin, viral DNA has been detected in lower frequencies
among respiratory secretions, on oral and anogenital
mucosa, and in the digestive tract [36–41]. The exact mode
of transmission remains to be elucidated and could involve
cutaneous, fecal-oral, mucosal, or respiratory routes.
Importantly, although widely prevalent, active MCPyV
infection appears to be asymptomatic and with the
exception of MCC, this virus has not yet been convincingly
associated with any other human disease.
Role of MCPyV in Pathogenesis of MCC
Cancer-associated viruses may contribute to carcinogenesis
directly via expression of viral oncogenes that promote cell
transformation or indirectly via chronic infection and
Curr Oncol Rep
inflammation, which may predispose host cells to acquire
carcinogenic mutations [42••]. Polyomaviruses are a genus
of non-enveloped viruses with a circular double-stranded
DNA genome of approximately 5,000 base pairs. The
ability of certain polyomaviruses to transform mammalian
cells is well known. The best studied example is the SV40
polyomavirus that was originally discovered in the primary
monkey kidney cells used to prepare polio vaccines.
Alarmingly, SV40 was found to induce multiple tumors in
newborn hamsters . Fortunately, despite their preva-
lence, the known polyomaviruses other than MCPyV have
not been associated with formation of any human tumors.
Typically, human polyomavirus infection is asymptomatic
except in immunosuppressed individuals who can develop
nephropathy (BK virus) or progressive multifocal leukoen-
cephalopathy (JC virus). In humans, MCPyV is the first
polyomavirus with demonstrated integration into genomic
DNA. Several significant observations suggest that MCPyV
contributes to the pathogenesis of MCC (Fig. 1): 1) it is
present in a substantial portion of MCC tumors [21••]; 2)
monoclonality of MCPyV integration in MCC tumor cells
suggests viral integration is an early event in tumorigenesis
[21••]; 3) T-antigen transcripts and oncoproteins are
expressed in most MCC tumors ; 4) the MCPyV LT-
antigen expressed in MCC tumors is truncated due to
mutations that preserve critical cell-cycle progression func-
tions, but eliminate cell-lethal virus-replication activities
[44••]; and 5) persistent expression of these MCPyV proteins
is required for continued growth of MCC cell lines in vitro
[26•, 98]. These findings strongly suggest that MCPyV plays
a key role in MCC carcinogenesis rather than merely being a
passenger virus that secondarily infects tumor cells.
The MCPyV LT-antigen appears to retain the major
conserved features of other polyomavirus LT-antigens, in-
cluding the DnaJ motif (binds to heat-shock proteins) and the
Fig. 1 Although infection with MCPyV is common, a progression of
several rare mutagenic events and escape from immune surveillance
likely precede the development of Merkel cell carcinoma (MCC).
Infection with MCPyV occurs early in childhood , is clinically
asymptomatic, and likely induces an appropriate humoral and cellular
immune response. Ultraviolet (UV) radiation or other environmental
mutagens may mediate virus integration into the host genome and
large T (LT)-antigen truncation mutations [44••]. These sequential
mutational events result in persistent T-Ag expression (brown stain
with IHC anti-LT antibody, CM2B4) that plays a key role in MCC
pathogenesis [26•, 42••, 46]. Importantly, in parallel, local, systemic,
or tumor-induced loss of immune surveillance may allow for an
unsupervised increase in both wild-type virus burden and T-Ag–
dependent MCC disease. Oftentimes, disease progression can be
monitored via immune biomarkers such as anti–T-Ag antibody levels
[60•], and disease outcome can be predicted by levels of CD8 T-cell
Curr Oncol Rep
the origin-binding and helicase/ATPase domains (promote
viral replication) [44••]. These various domains allow the
polyomaviruses to use host cell machinery for viral genome
replication, but can also target tumor suppressor proteins
resulting in cellular transformation . The LT-antigen
transcripts are commonly expressed in MCC tumors [44••].
However, tumor-specific truncating mutations retain LT-
antigen DnaJ and LxCxE motifs that promote cellular
growth, but eliminate origin-binding and helicase domains
that are essential for production of progeny virions [44••].
This acquired inability of tumor-derived LT-antigen to
initiate constitutive viral genome replication protects virus-
infected tumor cells from apoptosis triggered by DNA-
damage response mechanisms.
The mechanisms by which MCPyV may contribute to
MCC carcinogenesis continue to be elucidated. MCPyV T-
antigen appears to be essential for cell survival among
tumors infected with the virus. In MCPyV-infected MCC cell
lines and xenograft models, the expression of T-antigen
appears to be essential for sustained proliferation; knockdown
of this viral protein leads to growth arrest and/or cell death
while restoration of T-antigen expression rescues cell growth
[26•, 46, 98]. Furthermore, interaction with the retinoblasto-
ma (Rb) tumor suppressor protein appears to be critical to the
observed growth-promoting effects of LT-antigen .
Immunohistochemistry (IHC) data from human MCC tumors
and MCPyV LT-antigen expression, with LT-antigen–positive
MCC tumors also expressing Rb and 87% of LT-antigen–
negative tumors being Rb-negative as well [47, 48]. Similar to
the well-characterized interactions between SV40 LT-antigen
and the Rb family of proteins (Rb, p107, p130), the MCPyV
LT-antigen is likely to sequester hypophosphorylated Rb that
usually binds to E2F transcription factors. This sequestration
of Rb allows E2F-mediated transcription that leads to the
entry of the cell into S-phase. The integrity of the DnaJ and
the LxCxE motifs is required for this mechanism in SV40,
and the retention of these domains (with intact Rb-binding
ability) in the truncated MCPyV LT-antigen is consistent with
this mechanism being relevant to MCC pathogenesis.
The other putative mechanism by which polyomaviruses
contribute to transformation is interference with the p53
tumor suppressor pathway. The usual functions of p53 are
not conducive to viral replication as p53 transactivates
genes that lead to cell cycle arrest, which could deprive the
virus of essential replication factors. Additionally, active
p53 could lead to cellular apoptosis in response to the
presence of viral or cellular oncoproteins. In order to
complete their normal infectious cycles, the polyomaviruses
have developed the ability to block p53 function through
several mechanisms. The bipartite domain of the SV40 LT-
antigen can bind directly to the specific DNA-binding
domain of p53, hence interfering with p53-dependent gene
transcription [49, 50] (this binding has also been shown to
increase the half-life and steady-state levels of p53 in cells
). As the MCPyV LT-antigen seems to be prematurely
truncated in the MCC tumor cells lacking the helicase
domain and the supposed p53-binding sites [44••], the
significance of the p53 pathway in pathogenesis of
MCPyV-associated MCC is unclear. However, even if the
truncated T-antigen does not bind to p53, MCPyV may play
a role in suppressing p53 function in MCC tumors via other
mechanisms. For example, there is evidence that the
binding of T-antigen to p53 in SV40 may not be sufficient
to block p53 function and that other indirect mechanisms
(involving small T-antigen and/or the J-binding and Rb-
binding domains of the LT-antigen) are also important in
functional suppression of p53 [52, 53]. Consistent with
MCPyV somehow disabling p53 function in MCC tumors,
inactivating mutations in TP53 gene and/or overexpression of
55]. Moreover, recent studies have indicated an inverse
relationship between p53 expression and MCPyV viral
abundance in MCC tumors as well as p53 overexpression
potentially being associated with poor outcome [56, 57].
additional mechanisms by which MCPyV contributes to the
development/maintenance of MCC tumors. For example, the
small T-antigen (ST) that shares the N-terminus with LT-
antigen has recently been found to play an important role in
1) activating the AKT-mTOR signaling pathway, 2) inducing
loss of contact inhibition, and 3) promoting anchorage- and
serum-independent growth . While some of these
MCPyV-associated pathways may also be relevant to
MCPyV-negative MCC tumors (albeit via non-viral mecha-
nisms), the virus-associated MCC subgroup is likely to have
important biological distinctions from the virus-negative
subgroup. Understanding the molecular mechanisms that
contribute to disease progression in various MCC subgroups
will be crucial to the development of mechanism-based
targeted therapies for this disease.
Immunology of Merkel Cell Cancer
The discovery of MCPyVand its role in MCC pathogenesis
raises several interesting questions about interactions between
the host-immune system and MCC tumor cells. The sero-
epidemiologic data (discussed above) suggests that exposure
to MCPyV is widely prevalent and that viral capsid proteins
are recognized by the human immune system in infected
individuals [30, 31]. Also, as discussed above, MCC tumor
cells commonly express the MCPyV LT-antigen [44••, 58]
and the LT-antigen is essential for continued growth of cells
infected with the virus [26•, 46]. Despite this persistent
expression of viral proteins, however, MCC tumor cells are
Curr Oncol Rep
somehow able to evade the immune system. While this can be
explained by the presence of generalized T-cell dysfunction in
a small subset of MCC patients with comorbidities such as
HIVinfection, immunosuppressivemedications, or concurrent
hematologic malignancies, the vast majority (> 90%) of MCC
patients have no clinically apparent immune dysfunction .
Our understanding of host-virus immune interactions in MCC
pathogenesis is increasing rapidly with new insights into the
humoral and cellular immunity in MCC patients (Fig. 1).
Humoral Immune Response
Although the prevalence of antibodies to viral capsid proteins
(VP) in the general population is high, all studies have found
that IgG antibodies to MCPyV VP1 and VP2 are even more
prevalent in MCC patients [27, 30, 31, 59]. Interestingly, the
titer of antibodies to viral capsid proteins is typically higher
in MCC patients than in control populations [30–32]. This
finding is not attributable to increased viral capsid antigen
production by tumor cells because MCC tumor cells do not
express viral capsid proteins [31, 32]. One possible
explanation for higher antibody titers in MCC patients could
be exposure to a greater virus burden in MCC patients.
Supporting this hypothesis, the MCPyV DNA levels in
cutaneous swabs from MCC patients were found to be
significantly higher than levels in control population , and
another study reported a positive correlation between serum
MCPyV antibody titers and MCpyV DNA levels in skin
biopsies . The apparently higher virus burden in MCC
patients could possibly be a risk factor that predisposes to
subsequent development of MCC in these patients; alternative-
ly, the development of MCC could somehow have resulted in a
MCPyV-specific immunodeficiency that leads to the higher
virus levels on the skin of MCC patients (further discussed
below). Interestingly, higher anti-MCPyV capsid antibody titers
have also been associated with better progression-free survival
in MCC patients ; whether this indicates the presence of a
more robust host immune system remains unclear.
The limited serologic data from patients with MCPyV-
negative MCC tumors suggests that the majority of these
patients have been exposed to MCPyV , and in many
patients, antibody titers can be very high, similar to patients
with MCPyV-positive MCC . This raises the fascinat-
ing possibility of MCPyV infection possibly playing a role
in tumor initiation with subsequent selection for less
immunogenic, MCPyV-negative MCC tumor subclones in
these patients. Indeed, the heterogeneity of MCPyV DNA
or T-antigen expression levels in MCC tumors supports
immune selection within the tumors and is consistent with
the “hit and run” hypothesis for tumorigenesis in MCPyV-
negative MCC tumors.
As compared to antibodies to viral capsid proteins, anti-
bodies to MCPyV T-Ag oncoproteins are more specifically
associated with MCC; these antibodies are rarely detected in
the general population (< 1%) but appear to be present in a
substantial proportion (~40%) of patients with active MCC
[60•]. Importantly, the titer of antibodies to T-antigen
oncoproteins correlates strongly with the presence of MCPyV
DNA and the expression of T-antigens in MCC tumor cells
[60•]. Moreover, the antibody titer to T-Ag oncoproteins can
potentially serve as a biomarker of MCC disease burden; the
antibody titer drops rapidly after successful treatment of
MCC tumors and a rising titer in a previously treated patient
has been shown to herald disease progression prior to
development of symptoms [60•]. This apparent correlation
between the humoral response to T-antigens and MCC
disease burden is not completely unexpected because T-
antigen expression is selectively linked to MCC tumors.
Specifically, in contrast to viral capsid proteins that are
readily visible to the host humoral immune system, T-
antigens are not present in viral particles, are only expressed
after viral entry into host cells, are located in the nucleus ,
and are thus less likely to trigger an antibody response except
in the setting of dying or diseased tissue (such as a tumor that
persistently expresses T-antigens).
Cellular Immune Response
The presence of MCPyV T-antigen–specific antibodies that
appear to correlate with tumor burden in MCC patients [60•]
suggests ongoing expression of viral proteins in tumor cells
and their recognition by the adaptive arm of the immune
system. Histologic analyses have revealed the presence of
variable numbers of tumor-infiltrating lymphocytes (TILs) in
the MCC tumors with possible prognostic significance .
Our group has recently documented that intratumoral (but not
peritumoral) infiltration of CD8+ lymphocytes is an indepen-
dent predictor of improved survival among MCC patients. In
this study, unbiased gene expression analyses revealed over-
expression of immune response genes in tumors with favorable
prognoses. These immune response genes included genes that
encode components of cytotoxic granules (granzymes), chemo-
kines (CCL19), lymphocyte-activation molecules, and CD8
receptor molecules [63•]. Importantly, in an independent cohort
of 156 cases, patients with robust CD8+ intratumoral
infiltration had 100% MCC-specific survival as compared to
60% survival among patients with sparse or no CD8+
intratumoral infiltration [63•]. This evidence highlights the
important role of cellular immune responses in the natural
history of MCC and further explains the increased incidence of
MCC in patients with cellular immune suppression. Further-
more, we have identified MCPyV-specific epitopes that are
immunogenic to CD8 and CD4 Tcells isolated from blood and
MCC tumors . These epitopes and corresponding tumor-
specific T cell responses represent candidate targets for
therapeutic manipulation in MCC patients.
Curr Oncol Rep
Immune Evasion Mechanisms in MCC
Despite the expression of immunogenic virus-encoded
oncoproteins in the majority of tumors [44••, 60•],
MCCs that became clinically evident were significantly
able to evade host immune responses. According to the
cancer immunoediting hypothesis [64••], development of
tumors generally requires cancer cells to navigate suc-
cessfully through three distinct (and usually sequential)
phases of the interaction between the cancer and the host
immune system: 1) elimination phase, an immunosurveil-
lance phase in which the innate and adaptive immune
systems work together to detect the presence of nascently
transformed cells and destroy them before a tumor
becomes clinically apparent; 2) equilibrium phase, a
tumor dormancy phase in which the adaptive immune
system restrains the outgrowth of tumors and sculpts the
immunogenicity of the tumor cells; and 3) escape phase, a
tumor progression phase in which the tumor cells are able
to circumvent the host immune response manifesting as
clinically progressing tumors. The lack of a good animal
model for MCC pathogenesis and the inherent challenges
of conducting longitudinal studies in at-risk individuals
for a rare cancer render it difficult to study the precise
events during the elimination and equilibrium phases of
MCC tumorigenesis. However, the potential mechanisms
of immune escape by MCC tumors are becoming
increasingly apparent (Fig. 1).
The progression from equilibrium to the escape phase
may occur due to changes in tumor cell population that may
acquire new immune evasive characteristics or due to
changes in the host immune system that may get suppressed
either generally or more selectively toward the tumor cells.
Both of these broad mechanistic categories appear relevant
Tumor Cell Changes
Under the pressures of immune selection, MCC tumor
cells may acquire new features to become either “less
visible” to the immune system or “more resistant” to the
effects of the cytotoxic immune cells. The former may
occur via loss of tumor antigen expression. Cell surface
major histocompatibility complex class I (MHC-I)
serves to present intracellular peptides to CD8+ T
lymphocytes; specifically, viral oncoproteins expressed
in MCC tumor cells would be presented to T cells via
MHC-I. Indeed, multiple viruses (eg, adenovirus and
HSV) and virus-associated cancers (eg, Kaposi’s sarcoma,
cervical cancer) are known to directly or indirectly
down-regulate the expression of MHC-I as a key
mechanism of immune escape [65–70]. Besides MHC-I
loss, dysregulation of other components of cellular
antigen–presenting machinery such as the transporter
associated with antigen processing (TAP)  or down-
regulation of appropriate tissue-specific T-cell homing
signals may also preclude the presentation of persistently
expressed tumor antigens to T cells and need to be
investigated further in MCC. Indeed, our laboratory
findings suggest that 46% of MCC tumors exhibit a
“stalled phenotype” of lymphocytic infiltration where
CD8+ cells accumulated near the tumor-stroma border
but were unable to infiltrate into the tumors [63•]. Such
“peritumoral” T cells were not associated with significant-
ly improved survival. These features together likely lead
to poor visibility of the MCC tumor cells to the immune
system and may explain the sparse infiltrates of T cells in
most MCC tumors that are associated with poor outcomes
[63•]. Another important adaptation at the tumor cell level
that can result in immune escape is increased resistance of
the tumor cell to immune control mechanisms. Innate
immune signaling networks and tumor suppressor path-
ways share some key proteins such as p53  and cyclin-
dependent kinase inhibitor p21 . Due to this functional
overlap, the targeting of tumor-suppressor pathways by
MCC oncoproteins may also serve as an immune evasion
mechanism for MCC. In addition, tumor cells may secrete
proteins that interfere with the functioning of the immune
cells (discussed below).
Immune System Changes
Immunosuppression resulting in T-cell dysfunction may
predispose to the immune escape of transformed cancer cells;
however, clinically evident systemic immunosuppression due
to comorbidities such as post-transplant status, concurrent
hematological malignancy, HIV infection, etc. is present only
in fewer than 10% of MCC patients. What may be of even
greater relevance tothe pathogenesisofMCC, a disease ofthe
elderly population, could be the altered phenotype and
functional incapacity of an aging immune system that allows
the development and progression of the disease (Fig. 1). This
phenomenon of immunosenescence, an erosion of the
immune response with aging, is associated with phenotypic
and functional changes in both innate and adaptive arms of
the immune system, including a contracted repertoire of
naïve and cytotoxic T-cells and impaired function of effector
T cells . Ultraviolet radiation (UVR), another risk factor
for MCC, may not only promote critical LT-antigen
mutations and ST-antigen upregulation , but may also
play a key role in cutaneous immune system inhibition and
tolerance . Specifically, UVR has been implicated in
recruitment of regulatory T cells and in inhibition of antigen
presentation via direct damage to antigen presentation cells
(APCs) or via functional inhibition of APCs by cytokines
(interleukin 10, tumor necrosis factor-α) released by kerati-
Curr Oncol Rep
nocytes and mast cells [77, 78]. In addition to systemic
immune dysfunction contributing to immune escape, it is
likely that MCC tumor cells establish a local immune-
suppressive microenvironment in order to thrive. In this
scenario, immunologically sculpted tumor cell subclones may
overproduce immunosuppressive cytokines, such as TGF-β
, Fas-L , IL-10 , or inhibitors of T-cell responses
such as galectin-1  and indoleamine 2,3-dioxygenase
(IDO) . Tumors could also suppress proinflammatory
danger signals through pathways involving activated STAT3,
leading to impaired dendritic cell maturation , or could
downregulate the NKG2D receptor on immune effector cells
by secretion of soluble forms of the MIC NKG2D ligands
thereby attenuating lymphocyte-mediated cytotoxicity .
Tumor cells may also facilitate the generation, activation, or
function of immunosuppressive cells , such as CD4+
CD25+ regulatory T cells (T-regs)  or myeloid-derived
suppressor cells . T-cell exhaustion, originally described
in the context of chronic viral infection in mice [89, 90], is
being found to be increasingly relevant to human cancers. In
response to chronic antigen exposure, antigen-specific CD8+
T-cells often develop an exhausted phenotype with poor
effector function, sustained expression of inhibitory recep-
tors, and a transcriptional state distinct from that of
functional effector or memory T cells. The final stage of
exhaustion may involve physical deletion of antigen-specific
T cells [89, 91]. In the context of viral infection, more severe
CD8+ T-cell exhaustion has been correlated with higher viral
load. Moreover, in the setting of the same viral load, epitopes
that were present in larger amounts led to more extreme
exhaustion and/or deletion than epitopes present in smaller
amounts . This phenomenon may possibly be relevant in
MCC as well and could explain the observed higher MCPyV
viral load on the skin of MCC patients as compared to the
general population (discussed above) if MCPyV-specific T
cells are exhausted by chronic antigen exposure in the
tumors and hence fail to suppress MCPyV colonization .
The interaction of programmed death (PD)-1 expressed on T-
cells with its ligand B7H1 or PDL-1 is an important
mechanism of T-cell exhaustion  that could be harnessed
for therapeutic purposes.
Moving Toward Biology-Driven Immunotherapy
The discovery of the MCPyVand the increasing recognition
suggest several new targets for therapeutic exploration;
rational immunotherapeutic approaches can possibly advance
outcomes for this aggressive disease. The critical role of viral
oncoproteins in tumorigenesis of MCPyV-positive MCC
tumors and the resultant cellular expression of viral peptides
could not only be exploited to develop virus-targeting
therapies interfering with the function of the oncoproteins,
but also be harnessed to stimulate immune responses against
virus-infected tumor cells. As an example, the T-antigen–
specific antibody response is confined to a 78 amino acid N-
terminus domain shared by the small and large T-antigens
[60•], which could provide a suitable vaccine or adoptive T-
cell therapy target. Similarly, other non-viral tumor-
associated antigens such as survivin  or the oncoprotein
HIP1 that interacts with c-KIT  may also be suitable
immunotherapy targets. Immunostimulatory cytokines, such
as interferons, interleukin (IL)-2, IL-12, IL-15, or IL-21,
could be delivered systemically or intratumorally to coun-
teract immune evasion mechanisms employed by MCC
tumors. A phase 2 trial using intratumoral delivery of IL-
12 plasmid DNA followed by in vivo electroporation of
MCC tumors will be opening to accrual soon. Other
therapeutic agents that look appealing to investigate for
MCC treatment include CTLA-4 receptor–blocking agents
such as Ipilimumab (recently approved by the FDA for
metastatic melanoma), drugs targeting the PD-1/PDL-1
pathway to reverse immune exhaustion of infiltrating
lymphocytes, or drugs targeting the co-stimulatory 4-1BB
pathways that could promote T-cell infiltration, proliferation,
and cytokine production [95, 96].
Given the heterogeneity of MCC tumors and individual
variations in host immune systems, it is unlikely that one
single approach will be effective in all patients. Rather, a
combination of various strategies and personalization to the
unique biologic characteristics of MCC tumors in individual
patients will be required. Nevertheless, it is an exciting time
for investigation of novel targeted and/or immune therapies in
this fascinating malignancy.
our understanding of MCC pathogenesis. The immune
system appears to be playing a major role in MCC
biology with increasing evidence of virus-specific
cellular and humoral immune responses that influence
the prognosis of MCC patients. MCC tumors are able to
evade the immune system by establishing a local
immunosuppressive microenvironment. Understanding
the mechanisms of immune evasion by MCC tumors
will offer opportunities for development of biologically
driven therapies to improve patient outcomes from this
often lethal virus-associated cancer.
equally to this manuscript.
Shailender Bhatia and Olga Afanasiev contributed
No potential conflicts of interest relevant to this article
Curr Oncol Rep
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