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Review article
AllergoOncology: the role of IgE-mediated allergy in cancer
Before their identification as immunoglobulin E (IgE)
antibodies (1–4), research on ÔreaginsÕwas conducted
during five decades (5–7). Since this era, allergology and
parasitology have been traditionally considered as a
whole and this notion helped in evolving a lively picture
of the IgE-mediated immune response. It is, however,
more or less neglected today that the association of
allergic diseases and tumor occurrence has been discussed
already very early (8, 9). In the 1950s, precise experiments
investigated Ôallergic responsesÕtowards tumor trans-
plants (10). Consequently, the observed immunological
phenomena were even termed tumor allergy (11). The
discussion went on asking about the biological relevance
of tumor allergy for tumor progression (12, 13), until a
negative association between allergy and cancer was
announced for the first time (14). Later, the IgE levels and
atopy reactions in the skin of cancer patients were
examined (15, 16), finally rendering knowledge that the
prevalence of atopy was decreased in cancer patients (17).
Passive anaphylaxis or weekly injections of histamine and
serotonin inhibited tumor growth in a transplant mouse
model, pointing towards a possible role of anaphylactic
Epidemiological studies have suggested inverse associations between allergic
diseases and malignancies. As a proof of concept for the capability of immu-
noglobulin E (IgE) to destruct tumor cells, several experimental strategies have
evolved to specifically target this antibody class towards relevant tumor antigens.
It could be demonstrated that IgE antibodies specific to overexpressed tumor
antigens have been superior to any other immunoglobulin class with respect to
antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP)
reactions. In an alternative approach, IgE nonspecifically attached to tumor cells
proved to be a powerful adjuvant establishing tumor-specific immune memory.
Active Th2 immunity could also be achieved by applying an oral immunization
regimen using mimotopes, i.e. epitope mimics of tumor antigens. The induced
IgE antibodies could be cross-linked by live tumor cells leading to tumoricidic
mediator release. Thus, IgE antibodies may not only act in natural tumor sur-
veillance, but could possibly also be exploited for tumor control in active and
passive immunotherapy settings. Thereby, eosinophils, mast cells and macro-
phages can be armed with the cytophilic IgE and become potent anti-tumor
effectors, able to trace viable tumor cells in the tissues. It is strongly suggested
that the evolving new field AllergoOncology will give new insights into the role
of IgE-mediated allergy in malignancies, possibly opening new avenues for
tumor therapy.
E. Jensen-Jarolim
1
, G. Achatz
2
,
M. C. Turner
3
, S. Karagiannis
4
,
F. Legrand
5
, M. Capron
5
,
M. L. Penichet
6
, J. A. Rodrguez
7
,
A. G. Siccardi
8
, L. Vangelista
8
,
A. B. Riemer
1
, H. Gould
4
1
Department of Pathophysiology, Center of
Physiology, Pathophysiology and Immunology,
Medical University Vienna, Austria;
2
Division of
Genetics and General Biology, Hellbrunnerstraße,
Salzburg, Austria;
3
McLaughlin Centre for
Population Health Risk Assessment, Institute of
Population Health, University of Ottawa, Canada;
4
KingÕs College London, UK;
5
Unit Inserm 547,
Universit Lille 2, Institut Pasteur de Lille, France;
6
Division of Surgical Oncology, Department of
Surgery; Department of Microbiology, Immunology,
and Molecular Genetics; and the Jonsson
Comprehensive Cancer Center, David Geffen School
of Medicine, University of California, LA (UCLA),
USA;
7
Division of Surgical Oncology, Department of
Surgery; David Geffen School of Medicine,
University of California, LA (UCLA), USA;
8
Dibit,
San Raffaele Scientific Institute and Department of
Biology and Genetics, University of Milan, Italy
Key words: AllergoOncology; cancer; eosinophils; IgE;
tumoricidic.
Erika Jensen-Jarolim
IPP– Department of Pathophysiology
Center of Physiology, Pathophysiology and
Immunology
Medical University Vienna
Waehringer G. 18
1090 Vienna,
Austria
Accepted for publication 25 March 2008
Allergy 2008: 63: 1255–1266 2008 The Authors
Journal compilation 2008 Blackwell Munksgaard
DOI: 10.1111/j.1398-9995.2008.01768.x
1255
reactions in tumor immunity. Interestingly, an immuno-
histochemical study on the distribution of immunoglob-
ulin classes in head and neck cancer revealed IgE
antibodies to be the most abundant class, fixed in the
cancer tissues on dispersed macrophage-like cells (18).
This work suggests that IgE may have a natural surveil-
lance function in malignancies. Advancements in immu-
nology and molecular biology enable us today to go one
step further and exploit this knowledge for developing
IgE-based targeted cancer therapies.
This review aims at giving a comprehensive overview
on recent epidemiological and experimental evidence for
the occurrence of Th2-type immune mechanisms in tumor
disease. Moreover, also targeted therapies with IgE
antibodies and vaccination strategies will be discussed
as a novel perspective to combat cancer.
IgE antibodies: prime target unknown
IgE is an evolutionary conserved member of the Ig family
with the highest determined affinity to receptors (19–22)
and antigens among all antibody classes (23). The titer of
IgE is very low (nano- to micrograms per milliliter range) in
plasma of normal healthy individuals and of normal
laboratory mouse strains, but IgE is most prominent in
epithelia and mucosa where it is bound to specific receptors
on very potent effector cells like eosinophil or basophil
granulocytes and mast cells. This suggests that IgE plays a
role in local (rather than systemic) immune defence
mechanisms. In these days, IgE is best known for its
strong, unwanted effector functions, in the form of allergic
reactions (19). However, the prime target for IgE is still
unknown. From an evolutionary point of view, IgE is
conserved and can be found in all mammalia, including
monotremata (24). It therefore originated at least 160
million years ago, possibly even more than 300 million
years ago (25), from a gene duplication of IgY, in which the
anaphylactic and opsonic activities of IgY were separated,
giving rise to IgE and IgG, respectively (26). Apparently, in
an evolutionary sense, anaphylactic defence mechanisms
are needed. The division of anaphylactic and opsonic
activities in separate genes allowed principally a tighter and
more specific control of both immune mechanisms.
In the recent past, five B-cell specific control mecha-
nisms have been described that indicate a tight control of
the IgE response, in agreement with the arguments shown,
and that are different from the opsonic type of response.
1. IgE has the shortest free serum half-life (t
½
)ofall
immunoglobulins averaging 12 h in mice (27) and
1–5 days in humans (28, 29), limiting the danger of a
systemic anaphylactic reaction. After production
serum IgE is rapidly bound by the high-affinity
FceRI on the surface of effector cells like mast cells
and basophils where it acquires a long half-life time
(weeks to months).
2. Several studies with mice deficient of, or overex-
pressing the low-affinity IgE receptor CD23, clearly
demonstrated CD23Õs role as a major negative
feedback regulator of IgE production. Yu et al. (30)
showed that disruption of the CD23 gene led to
increased specific IgE levels after immunization with
2,4-dinitrophenyl-ovalbumin (DNP-OVA), while
IgG1 levels were twice as high, specific IgE levels
were 6–12 times higher in these CD23
–/–
mice.
3. Two mIgE knock-out mice (31) underlined the key
function of the IgE receptor in the regulation of IgE
expression in vivo and by analyzing the phenotypes
of the mice strains it could clearly be demonstrated
that the antigen receptor is the only device for an
effective antigen presentation (32, 33). In the first
strain, the intracellular domain of IgE was removed
except for three amino acids (Lys, Val, Lys;
KVKDtail line). The cytoplasmic domain of IgE in
these mice is the same as that of mIgM and mIgD. In
the second line, both the intracellular and trans-
membrane domains of IgE (DM1M2 line) are lack-
ing (Fig. 1). In DM1M2 mice serum IgE is reduced
to less than 10% of normal mice, while KVKDtail
mice show a reduction of 50%, reflecting a serious
impairment of the IgE-mediated immune response.
Upon stimulation of isolated spleen cells of wild
type, DM1M2 and KVKDtail mice with LPS and IL4
in vitro, concentrations of IgE and IgG1 in the
culture supernatants were comparable in wild-type
and mutant mice. These results imply that the
reduced IgE titers found in both mutant lines are
solely a reflection of the loss of biological activities
associated with the transmembrane and cytoplasmic
domains of IgE.
4. The process of alternative polyadenylation restricts
surface IgE expression and thus influences further
serum IgE production. mRNA for the membrane
form of both the murine and human epsilon (e)
heavy chain is poorly expressed, compared with the
mRNA for the secreted form in activated, mIgE-
bearing B cells (32, 34).
5. Finally, also the establishment of humoral memory is
limited for IgE responses in vivo. IgE plasmablasts
have an intrinsic, lower chance to contribute to the
long-lived plasma cell pool and thus to humoral
immunologic memory than IgG1 plasmablasts.
Apparently, an IgE immune response is in all stages
of the response negatively regulated. The IgE anti-
bodies may have strong effector functions, but the
IgE response is slow and limited in developing
memory responses.
Therefore, the IgE antigen receptor itself plays a major
role in the decision of quantity and quality of serum IgE
antibodies and besides, is probably the most powerful
surface receptor, influencing developmental processes of
the cell. It was suggested that the signaling cascade
Jensen-Jarolim et al.
2008 The Authors
1256 Journal compilation 2008 Blackwell Munksgaard Allergy 2008: 63: 1255–1266
underlies a permanent stochastic fluctuation, which
induces no cellular response, but is important for main-
tenance of cell viability [reviewed in (35)]. Taken together,
all these observations point towards the existence of
mechanisms to restrain potentially dangerous, but appar-
ently necessary, serum IgE titers.
Epidemiological association of IgE and malignancies
Hints from clinical observations triggered numerous
epidemiological studies to examine the potential associ-
ation between a history of IgE-mediated allergy and
cancer. These studies, and important methodological
considerations, were summarized in recent review articles
(36, 37). Although the results are not entirely clear, there
is some limited evidence to suggest a possible inverse
relation.
In perhaps the largest study of its kind, over 1.1 mil-
lion US adults, for whom self-reported physician-diag-
nosed asthma or hay fever status at baseline was known,
were followed-up for a period of 18 years (38). Results
suggested a significant inverse association between a
history of both asthma and hay fever, possibly the most
relevant indicator of allergic status examined here, and
all cancer mortality [relative risk (RR) = 0.88, 95%
confidence interval (CI) 0.83–0.93]. The risk of mortality
from several site-specific cancers was also reduced, with
that for colorectal cancer significant (RR = 0.76, 95%
CI 0.64–0.91). In a separate analysis of never smokers,
results were similar, although they attenuated slightly
and were no longer significant. Results from other
smaller prospective studies were mixed (39–42), includ-
ing some who used skin-prick testing to define allergic
status (43–45). Conversely, one study recently followed
70 136 patients for whom data on total serum IgE
levels were known and 57 815 patients for whom data
on allergen-specific IgE levels were known (46). No
association with cancer incidence was reported for either
measure.
Case-control studies using self-reported allergy history
information have also suggested several potential inverse
associations between allergic status and site-specific
cancers including pancreatic (47) and glioma (48) with
the magnitude of the effect ranging from approximately
30–40% reductions in risk. Inverse associations were also
reported in studies of childhood leukaemia (49–51) or
myeloma of adults (52). Case-control studies, measuring
allergen-specific IgE in cases following cancer diagnosis,
have reported mixed findings. Wiemels et al. (53)
reported inverse associations between glioma and total
IgE levels [odds ratio (OR) elevated total IgE = 0.37,
95% CI 0.22–0.64) and allergen-specific IgE levels,
particularly food IgE (OR = 0.12, 95% CI 0.04–0.41).
Melbye et al. (54), in a large multi-center study, reported
a significant inverse association between allergen-specific
IgE and non-HodgkinÕs lymphoma (NHL; OR = 0.68,
95% CI 0.58–0.80). However, upon further analysis,
NHL dissemination in cases was found to be inversely
associated with specific IgE, and in a second, prospective,
study, an inverse association was found only immediately
prior to NHL diagnosis, leading the authors to conclude
that inverse associations reported in previous studies were
likely due to the suppression of the allergic response in
NHL cases. Positive associations were reported between
allergen-specific IgE and both prostate (55, 56) and breast
cancer (57).
The following discussion will focus on the elucidation
of the immunological mechanistic principles potentially
underlying the epidemiological observations.
IgE and its receptors: interaction with intratumoral effector cells
If IgE antibodies (Abs) were directed against tumor-
associated antigens (TAA) they could mediate the cell-to-cell
association between tumor and effector cells, possibly
resulting in antibody-dependent cellular cytotoxicity
(ADCC) and antibody-dependent cellular phagocytosis
(ADCP). For these reactions, the high- and low-affinity
receptors, FceRI and CD23 (19, 20), on effector cells being
on site in the tumor tissue are crucial. The affinity of IgE for
FceRI is by two to five orders of magnitude higher than that
of IgG for their receptors, making IgE the only antibody
signal transduction
AG processing
Figure 1. In the immunoglobulin E (IgE)
KVKDtail
mouse strain,
the intracellular domain of IgE was removed except for the three
conserved amino acids (Lys, Val, Lys). Thus, the cytoplasmic
domain of IgE in these mice is identical to the cytoplasmic tail
expressed by mIgM and mIgD. In the IgE
DM1M2
line, both the
intracellular and transmembrane domains of IgE are lacking.
The cytoplasmic tails of the membrane immunoglobulins have
the capacity to bind proteins, committing a signal transduction
pathway which is independent of the well-known Ig-a/Ig-b
pathways. The green domains represent Ig heavy chains, red
domains indicate Ig light chains, white domain indicates trans-
membrane domain, clewed domain indicates intracellular tail
and pink and brown domains indicate Ig coat proteins Ig-a/
Ig-b.
AllergoOncology: the role of allergy in cancer
2008 The Authors
Journal compilation 2008 Blackwell Munksgaard Allergy 2008: 63: 1255–1266 1257
class being strongly retained by effector cells in the absence
of antigen. Thus, IgE engaged to FceRI in tissues could be
more effective in anti-tumor responses than IgG and its
receptors. FceRI-expressing monocytes exerted primarily
ADCC towards tumor cells. Upon upregulation of FceRI
by preincubation with IgE specific for the ovarian tumor
antigen folate receptor, an increase in ADCC was observed
(58–60).
Recent strategies, aiming at enhancing the anti-tumor
responses of T cells, exploited the high affinty of the IgE–
FceRI complex by transfecting T lymphocytes with a
chimeric molecule comprising the extracellular domain of
FceRI with the cytoplasmic domains of CD28 and T cell
receptor zeta chains (61). FceRI-expressing human T cells
engaged by tumor-specific IgE monoclonal anti-
body (mAb) secreted cytokines, proliferated and medi-
ated cytotoxic functions also in vivo following antigen
ligation.
CD23, the low-affinity IgE receptor, exists in two
forms, CD23a and CD23b, differing at the cytoplasmic
N-terminus which contains different signaling motifs that
determine their functions (62). The expression of CD23b
by interleukin (IL)-4, e.g. derived from natural killer cells
in breast cancer tissues, is induced on various cells,
notably mast cells, basophils and monocytes (63, 64). By
the way, IL-4, like IL-13, is also an important switch
factor for IgE production, the latter being also directly
derived from cancer cells (65). Engagement of CD23b by
IgE–antigen complexes promotes monocyte/macrophage
activation, induces nitric oxide synthase (iNOS) and
generates pro-inflammatory cytokines (66, 67). CD23b
mediates IgE ADCP (63) and may thereby, besides its
control function for IgE production (30), mediate tumor
cell death. This function has been confirmed as a CD23–
IgE complex-driven mechanism of engaging monocytes in
ADCP of ovarian tumor cells upregulated by IL-4 (59).
IgE antibodies can thus engage both cell surface IgE
receptors, FceRI and CD23, and activate several lines of
effector cells against tumor cells in vitro and in vivo.
Indeed, solid tumors are associated with inflammatory
responses involving the infiltration by not only B and
T lymphocytes, neutrophils and natural killer cells, but
also mast cells, macrophages and eosinophils expressing
the IgE receptors (68).
It has been shown that mast cells infiltrate the invasive
fronts of tumor lesions where their degranulation pro-
motes the remodeling of tissue architecture, angiogenesis,
tumor cell growth and metastasis (69). The location of
mast cells away from the core of solid tumors, loss of local
tissue architecture and production of angiogenic factors
[vascular endothelial growth factor (VEGF), basic fibro-
blast growth factor (bFGF), IL-8, tumor necrosis factor
(TNF)a, matrix metalloproteinase (MMP)-9], may play a
role in their inability to target tumor cells. Mast cells have
even been described to be a negative prognostic marker in
Merkel cell carcinoma (70). Moreover, there is genetic
evidence for a role of mast cells for tumor expansion in a
pancreatic islet cell tumor model (71). On the other hand,
the intensity of mast cell activation/response in the
absence of antigenic stimuli may also contribute to tumor
cell death (69, 72), e.g. by releasing preformed proapop-
totic TNFaupon triggering (73, 74), as well as histamine,
which acts to promote or inhibit tumor growth dependent
on the type of histamine receptor expressed (75).
Tumor-associated macrophages (TAM) are found in
virtually all types of tumors and can comprise more than
50% of the total tumor mass (76). Blood monocytes are
recruited to the tumor sites by chemokines and cytokines
released by tumor cells and neighboring endothelial cells.
They can be stimulated to either kill tumor cells and
release angiostatic compounds, or, like mast cells, pro-
mote tumor growth and metastasis by producing angio-
genic factors and MMP (77). Immunohistochemical
studies in breast cancer confirm the presence of CD23
on the surface of TAM and the expression of iNOS (78,
79). Cytotoxic mediators such as NO are produced by
monocytes/macrophages in cancer tissues at levels below
those required for tumor cell cytotoxicity, so that the
balance of NO production has been suggested to be
tipped in favor of tumor growth (80, 81). In contrast,
recent studies report that NO is necessary to mediate the
antiangiogenic effect of TNF via its receptor TNFR2 in
the tumor (74). It has been suggested that these potential
cytotoxic effects could be enhanced to activate TAM
against tumor cells. Activation signals by tumor antigen-
specific IgE may ÔawakeÕTAM to this end.
Like macrophages, also other antigen-presenting cells
such as B lymphocytes, Langerhans cells and dendritic
cells present in tumor infiltrates express CD23 and/or
FceRI and can be activated by locally secreted lympho-
kines as well as tumor antigen-specific IgE. All these
events can initiate IgE antibody-dependent antigen pre-
sentation to autologous T cells and induce active immu-
nity (82–86). Therefore, although the mechanisms by
which IgE antibodies exert their anti-tumor effects against
cancer cells are only starting to emerge, it seems clear that
all the ingredients necessary for an IgE-mediated response
are in place in human malignant disease.
Eosinophils: exquisite effectors in anti-tumor immunity
Eosinophils are today considered as multifunctional
leukocytes, involved in inflammatory processes, tissue
remodeling as well as in modulation of innate and
adaptive immunity (87). Typically, differentiation and
function of eosinophils is regulated by the CD4 Th2
cytokines IL-3, IL-5 and granulocyte macrophage (GM)-
colony-stimulating factor (CSF), and may be regarded as
typical cells in type 2 immunity (88). Eosinophils express
membrane receptors involved in adaptive immune re-
sponses like Fc receptors for IgG, IgA or IgE, class II
major histocompatability complex (MHC) or co-stimu-
latory molecules including CD86 and CD28 that allow
interactions with lymphocytes and antigen-presenting
Jensen-Jarolim et al.
2008 The Authors
1258 Journal compilation 2008 Blackwell Munksgaard Allergy 2008: 63: 1255–1266
cells (89). Triggering eosinophils by engagement of
receptors for cytokines, immunoglobulins or complement
lead to the secretion of numerous cytokines [IL-2, -4, -5, -
10, -12, -13, -16, -18, (transforming growth factor (TGF)-
a/b], chemokines (RANTES, eotaxin) and lipid mediators
(platelet-activating factor, leukotriene C4). Moreover,
release of Th2 or Th1 immunoregulatory cytokines and
cationic proteins can be specific and dependent upon the
nature of stimulus (90, 91). In their specific granules,
eosinophils store great quantities of cytokines and
cationic proteins, known to be highly cytotoxic mediators
[reviewed in (92)]. They can also generate reactive oxygen
species (ROS). This high cytotoxic potential can lead to
deleterious effects in inflammatory and allergic processes,
and eosinophil numbers have also been documented to be
elevated in peripheral blood and/or infiltrate the tissues in
some malignant disorders (93, 94). This eosinophilia is
named TATE for Ôtumor-associated tissue eosinophiliaÕ.
High infiltrating eosinophil counts were associated with a
significantly better prognosis in esophageal squamous cell
carcinoma, gastric cancer, head and neck cancer and
colorectal carcinoma (95–99). Activated, they may more-
over prevent the metastasis potential of prostate cancer
(100, 101). Although TATE may have favorable prog-
nostic value, little is known however on the exact role
played by eosinophils in anti-tumor responses.
Recent in vitro (102) and in vivo (103, 104) studies have
suggested a potential tumoricidal activity of eosinophils.
For the evaluation of the tumoricidal activity of human
eosinophils two tumor cell lines, a T lymphoma and a
colorectal adenocarcinoma, Jurkat and Colo-205 respec-
tively, were used. Several in vitro arguments allow
postulating that human eosinophils purified from the
peripheral blood of different eosinophilic donors are able
to use effectively their cytotoxic potential towards these
human tumor cell lines by inducing their apoptosis in
different ways (Capron et al., unpublished observations).
Indeed, eosinophils from allergic donors are more effi-
cient, and eosinophils from patients with HES (hyper
eosinophilic syndrome) less efficient than eosinophils from
normal donors. The heterogeneity of eosinophil-mediated
tumor cytotoxicity according to eosinophil donors led to
the suggestion that allergic patients are more efficient
towards tumor development with a potential tumor
sensing role of IgE. Experiments in the Capron-lab are
in progress to define the respective cytotoxic properties of
specific eosinophil cationic proteins vs tumoricidal mole-
cules shared with other effector cells, such as granzymes
and perforin. Besides IgE-dependent tumor cell cytotox-
icity of eosinophils (59), there is evidence for IgE
antibody-independent killing mechanisms.
IgE for passive immunotherapy of cancer patients?
In the late 1980s, experiments comparing the capacity of
various mouse/human chimeric antibodies of different
classes and subclasses to elicit ADCC and complement-
dependent cytotoxicity (CDC), found that IgG1 was
more effective than the other IgG subclasses tested
suggesting its superior tumoricidal effect (105). In con-
trast to IgG, human IgE is incapable of directing
complement activation against the targeted tumors
(106). The use of recombinant DNA technology has then
allowed the construction of recombinant IgG antibodies
that can recognize TAA and confer protection against
cancer cells by passive immunotherapy. The success of
these efforts has resulted in FDA-approved therapeutics
such as rituximab (Rituxan) and trastuzumab (Hercep-
tin) both with human IgG1 constant regions and
variable regions targeting CD20 (B-cell lymphoma
TAA) or HER2/neu (breast and ovarian cancer TAA),
respectively (107).
Coupled with the logical concern over IgE-induced
type I hypersensitivity, these results have demotivated
most researchers from further pursuing IgE for passive
immunotherapy. However, the use of IgE for the passive
immunotherapy of cancer would offer several advantages
over conventional IgG-based approaches, including its
high- and low-affinity receptors present on a broad
spectrum of effector cells, its capacity for antigen uptake
and presentation leading to a secondary immune
response. In contrast to IgE where serum concentrations
compose only 0.02% of the total antibody population,
IgG constitutes up to 85%, suggesting that a larger pool
of endogenous IgG competitors for cell surface receptors
could reduce the ADCC efficacy of a therapeutic IgG
dose (108). From this fact and its cytophilicity it may be
expected that lower passive doses of IgE antibody
preparations than necessary for IgG will be sufficient to
achieve therapeutic effects at the targeted tumor.
The first studies using IgE mAbs for the passive
immunotherapy of tumors were performed in the early
1990s (109). Using two IgE-producing hybridomas, Nagi
et al. (109) generated murine IgE antibodies targeting a
glycoprotein (gp36) of the mouse mammary tumor virus
(MMTV). Intraperitoneal injections of the monoclonal
IgE were given at 4-day intervals to CH3/HeJ mice to
treat a syngeneic subcutaneously injected MMTV-secret-
ing mammary carcinoma (H2712). After 6 or 8 weeks
of treatment, the monoclonal IgE therapy was capable of
preventing subcutaneous tumor development in 50% of
the animals treated, but did not protect mice exposed to
MMTV-negative mammary carcinoma cells (MA16/c).
However, this study did not offer side-by-side comparison
of IgE and IgG for the treatments of tumors. It was not
until the late 1990s that studies by Kershaw et al. (110)
investigated both the IgE- and IgG1-mediated growth
inhibition of solid tumors using the human colorectal
carcinoma (COLO 205) cell line. A murine IgE (30.6)
targeting an antigenic determinant on the colorectal
carcinoma cells was shown to transiently inhibit the
growth of COLO 205 cells injected subcutaneously into
SCID mice while both a mouse/human chimeric IgG1
AllergoOncology: the role of allergy in cancer
2008 The Authors
Journal compilation 2008 Blackwell Munksgaard Allergy 2008: 63: 1255–1266 1259
and IgE containing the (30.6) variable region and
corresponding human constant regions showed no effect.
The immune response against the COLO 205 tumors
directed by the murine IgE offered a robust yet transient
reduction of tumor growth using a dose of 1 lg per
mouse of IgE in contrast to the optimum dose of
4·250 lg per mouse required for IgG1. This effect
may be attributed to the superior affinity of IgE to its
receptor FceRI and to the usage of highly tumoricidic
effector cells. In fact, the lack of an anti-tumor effect
observed with the mouse/human chimeric IgE containing
human constant regions is not surprising as human IgE
does not cross-react with murine FceRI.
The potency of IgE interactions with effector cells and
their receptors in tumor cell killing has been demonstrated
using chimeric antibodies (MOv18 IgE and MOv18 IgG1)
against an ovarian tumor-specific antigen, folate binding
protein, expressed in 80% of ovarian cancers. In two
mouse xenograft models of human ovarian carcinoma,
treatment of the mice with IgE, combined with human
peripheral blood mononuclear cells (PBMC), had a
longer-lasting effect in restricting tumor growth than the
same treatment with IgG1 (105). In the second model,
grown orthotopically in nude mice, MOv18 IgE with
human PBMC, gave significantly greater protection than
PBMC alone, while MOv18 IgG
1
with human PBMC
offered no survival advantage (111). Immunohistochem-
ical studies of tumor sections showed the infiltration
of human monocytes/macrophages into tumor lesions,
associated with tumor necrosis and increased survival.
Although a number of studies have demonstrated the
potential of IgE in the passive immunotherapy of tumors,
most attempts have been riddled with limitations includ-
ing several incompatibilities between the mouse and
human immune systems in the domain of IgE-mediated
immunity (112). The complete potential of IgE-mediated
therapy that would be expected in humans has not been
achieved in many studies possibly because the expression
of FceRI in mice is limited to mast cells and basophils,
whereas in humans it is also expressed in monocytes,
macrophages, eosinophils, Langerhans cells and dendritic
cells. Moreover, the experiments described thus far using
mouse/human chimeric IgE for the treatment of tumor
xenografts in immune-suppressed mice suffered from a
limited supply of exogenous human PBMC; better results
may be potentially achieved in patients that have a fully
active immune system and a constant supply of effector
cells.
Some of the incompatibilities challenging IgE-mediated
immunity models have been solved with the development
of FceRI alpha chain transgenic mice. One of these mice
carries both, a human and a murine FceRI alpha chain
(113, 114), while in the other the murine FceRI alpha
chain is replaced by the human FceRI alpha chain (113,
114). The latter transgenic mouse exhibits the cell-specific
pattern of expression of the human alpha chain as well as
the correct structure of the receptor for each cell type.
This unique model can be potentially used in future IgE
immunotherapy studies in which a true IgE-directed
effector cell response could be mounted against a synge-
neic tumor model in vivo. Treatment of tumors using a
mouse/human chimeric IgE should generate a response in
mice closer to that of a human IgE response, but would
still be limited by the risk of a mouse anti-human
hypersensitivity response, preventing sequential adminis-
trations of chimeric IgE. These and other improvements
of transgenic models may soon provide a fully functional
in vivo readout system to test the efficacy of IgE against
various types of cancers in murine models.
IgE as adjuvant in tumor vaccination
Considering that the activation of the antigen–IgE–FceRI
axis profoundly affects the immune system both in its
cellular orchestration and programming, resulting in a
potent inflammatory state, an attempt of using IgE as a
potent adjuvant in anti-tumor vaccination has been
undertaken. In an initial study, the capability of targeting
mouse IgE on tumor cells and the consecutive effect on
tumor vaccination was assessed in C57BL/6 mice using a
T cell lymphoma line and an adenocarcinoma cell line
(115). Targeting of tumor cells was obtained exploiting
biotin–avidin bridges both in vitro, prior to cell admin-
istration, or in vivo by the three-step targeting method
(116). The use of biotin–avidin bridges eliminated the
need for IgE tumor specificity, however biotinylated IgG
anti-tumor antigen monoclonals were required to achieve
selective IgE targeting on tumor cells. Immunization
protocols were implemented in which irradiated tumor
cells (loaded with IgE or IgG) were administered,
followed by tumor cell challenge. Vaccinated mice
exhibited a strong tumor protection in the IgE-targeted
group, indicating that an IgE-specific adjuvant effect was
established. Conversely, nonimmunized mice or mice
immunized with IgG-targeted cells presented comparably
fast tumor growth and death. As IgE was absent during
tumor cell challenge, the protective effect should be
ascribed to the immune system stimulation upon the IgE-
targeted cell vaccination. Indeed, both eosinophils and
T cells (CD4
+
and CD8
+
) proved to be crucial for the
anti-tumor immunity, as their depletion led to abolish-
ment of tumor protection also in the IgE-treated mice. In
addition, dendritic cells loaded with tumor cell fragments
were found exclusively on draining lymph nodes of
IgE-treated animals (Siccardi et al., unpublished). This
represents a strong evidence for tumor antigen-loaded
dendritic cell migration from the tumor site to peripheral
lymph nodes, an important piece in the IgE-driven T cell
immune memory picture.
Based on these evidences, the anti-tumor IgE adjuvan-
ticity approach is being progressed trying to address three
major issues: (i) improvement of the vaccination strategy;
(ii) understanding IgE receptors involvement (FceRI and
Jensen-Jarolim et al.
2008 The Authors
1260 Journal compilation 2008 Blackwell Munksgaard Allergy 2008: 63: 1255–1266
CD23); and (iii) humanization of the reagents to move
towards clinical applications.
In view of the possibility to engineer modified vaccinia
virus Ankara (MVA) to produce recombinant anti-tumor
factors, MVA additive/synergic effect in combination
with IgE tumor cell loading was tested in mice immuni-
zation studies with encouraging results; in addition,
several IgE-targeting protocols have been tested, with
tumor cell haptenization and surface biotinylation as the
most promising ones (Nigro et al., in preparation). In
perspective, MVA being widely recognized as a safe and
promising tool for human therapy (117), its use in IgE-
based anti-tumor vaccination goes in the right direction
for future clinical trials. Use of recombinant MVA to
expressed membrane tumor antigens on the surface of
(IgE-loaded) infected tumor cells should then induce an
enhanced anti-tumor immunity. Most importantly, MVA
could be engineered to express membrane IgE (mIgE) on
the surface of tumor cells, exploiting the reported
capability by mIgE to activate FceRI (118). This strategy
would simplify the vaccination protocol of MVA and IgE
by fusing them into a single mIgE-expressing MVA.
Moreover, knowledge on the IgE–FceRI binding features
(119) allowed the production of a truncated heavy chain
mIgE (cleaved at the joint between the Ce2 and the Ce3
domain) that could represent the ultimate IgE version for
anti-tumor vaccination: guaranteeing FceRI activation,
preventing soluble IgE circulation and excluding antigen
binding. Testing FceRI a-chain knock out BALB/c mice
(120) in the MVA infection/IgE-loading tumor cell
vaccination system provided strong evidence on FceRI
importance for the IgE-orchestrated adjuvanticity
(unpublished observation). However, keeping in mind
the differences in FceRI expression between mouse and
human cell types, a humanized FceRI a-chain mouse
(113) is presently being investigated.
Overall, the mechanism behind IgE-driven tumor
vaccination appears to imply IgE–FceRI recognition, in
a tumor cell–FceRI
+
cell scenario. Following, it is highly
likely that tumor cell killing occurs, either directly by the
FceRI
+
-activated cells (mast cells/basophils) and/or by
the on-site recruitment of specialized killer cells such as
eosinophils. Cell killing releases tumor cell debris con-
taining tumor-specific antigenic determinant available for
dendritic cells that in turn transfer the information to
peripheral immune districts for the establishment and
consolidation of a tumor-specific immune memory
(Fig. 2).
From allergy to oncology: how to make a tumor antigen
an allergen
From the discussion shown, it is clear that IgE antibodies
targeted or fixed to tumor antigens – in contrast to overall
elevated IgE levels – cause a marked effect on tumor
development and growth. However, all these strategies
used passive applications of IgE. A combination of
knowledge in active cancer immunotherapy on the one
hand, and in basic allergy mechanisms on the other,
prompted recently the development of a vaccine that
would induce tumor-specific IgE in vivo. Two strategies
were combined: first, an epitope-specific vaccination
against the tumor antigen HER-2, rendering antibodies
with similar biological properties as the monoclonal
antibody trastuzumab (121). Second, an oral immuniza-
tion regimen discovered in food allergy research, resulting
in IgE induction (122–125).
Figure 2. Schematics of the mechanisms behind immunoglobulin E (IgE) adjuvanticity in anti-tumor vaccination. The IgE–FceRI
interaction is represented by the crystal structure of the FceRI-achain–IgE Ce3Ce4 complex.
AllergoOncology: the role of allergy in cancer
2008 The Authors
Journal compilation 2008 Blackwell Munksgaard Allergy 2008: 63: 1255–1266 1261
HER-2 is a member of the epidermal growth factor
receptor (EGFR, also know as ErbB) family. This
receptor is overexpressed in approximately 30% of breast
cancer patients and confers a detrimental prognosis in
the course of early as well as advanced breast cancer
(126). The monoclonal antibody trastuzumab (Hercep-
tin) targets this molecule, and beneficially influences
progression of early and advanced HER-2 overexpress-
ing tumors. In active cancer immunotherapy studies,
trastuzumab was used to generate an epitope-specific
vaccine targeting HER-2. Peptide mimics (so-called
mimotopes) were generated from the antibody-binding
site. These mimotopes induced trastuzumab-like IgG
antibodies in mice upon intraperitoneal immunization.
Importantly, actively induced antibodies upon mimotope
vaccination induce antibodies with similar biologic anti-
tumor features as the original antibody itself (121, 127,
128).
Second, food proteins can effectively lead to IgE
formation and sensitization when they persist the gastric
passage undegraded (129). Gastric digestion is impaired
in conditions of hypoacidity, as e.g. under anti-ulcer
treatment. Consequently, an oral immunization regimen
was developed that leads to induction of a Th2 bias in
mice, namely high levels of food-protein-specific IgG1
and IgE antibodies, eosinophilia and hypersensitivity of
skin and mucosa, when antigens are fed under concom-
itant gastric acid suppression (125, 130).
When the oral immunization regimen was adapted for
the mimotope vaccine construct, it could indeed demon-
strate that feedings of trastuzumab mimotopes under
anti-acidic conditions induced HER-2-specific IgE anti-
bodies in BALB/c mice. Apparently, this was the first
documented active induction of tumor-specific IgE
in vivo. The antibodies proved to be functional in an
allergologic mediator release assay, where mimotope-
induced IgE was found to react specifically with HER-2
overexpressing breast cancer cells. In an assay evaluating
the ADCC-mediating potential of the induced anti-HER-
2 IgE antibodies, they were shown to be effective in
mediating lysis of these breast cancer cells. The degree of
IgE–ADCC mediated by the sera correlated with the level
of HER-2-specific IgE detected by the mediator release
assay. These experiments show that it is possible to turn a
tumor antigen into an allergen (Fig. 3).
In the context of eliciting IgE towards self-antigens, it
is self-evident that safety issues are paramount, and the
risk of allergic reactions has to be carefully ruled out.
Similarly as on allergens, the optimal target antigen/
epitope should be present on the tumor cell surface in a
sufficient density to cause cross-linking of IgE antibodies
bound to the effector cells (131). On the other hand, the
target antigen should either not be shed into the blood-
stream, or its soluble form should not form aggregates
that could lead to undue effector cell activation and
systemic anaphylaxis. These issues will have to be
thoroughly monitored in future in vivo trials in the setting
of active as well as passive administrations of anti-tumor
IgE antibodies.
Taken together, it is feasible to induce IgE anti-tumor
antibodies by active immunization and it can be hypoth-
esized that for suitable antigens, this approach could be
developed into an easily applicable oral vaccination.
Conclusions
IgE antibodies favor the recognition of conformationally
intact antigens with a dense epitope display. Intact, viable
tumor cells fulfill these requirements because they over-
express antigens. Via interaction with its receptors on
numerous defence cells, IgE directs potent effector cells
into tumor tissues with proven tumoricidic activity. Thus
it can be hypothesized that IgE antibodies might phys-
iologically survey malignant cells. These principles will
hopefully in the future be exploited for vaccines and
passive antibody therapies.
Acknowledgments
This work was supported by grant PA-18238-B13 of the Austrian
Science Fund (FWF), by the Italian MURST (Cofin 2005), Uni-
versity of California Cancer Research Coordinating Committee
(CRCC), Susan G. Komen Breast Cancer Foundation, Howard
Hughes Medical Institute Gilliam Fellowship for Advanced Studies,
and UCLA MBI Whitcome Fellowship.
Figure 3. The principle of food allergy induction exploited for
oral cancer vaccination. When BALB/c mice were fed with
mimotopes for the important cancer antigen HER-2 under
concomitant anti-ulcer therapy, they developed immunoglobu-
lin E (IgE) specific for HER-2. The induced IgE was able to bind
to FceRI-positive RBL effector cells. Upon consecutive chal-
lenge with HER-2-positive SKBR-3 breast cancer cells, media-
tors were released which acted tumoricidic on the target cells.
The triggering was specific, as non-HER-2-expressing control
cancer cells (A432) were not able to lead to mediator release.
Jensen-Jarolim et al.
2008 The Authors
1262 Journal compilation 2008 Blackwell Munksgaard Allergy 2008: 63: 1255–1266
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