Interleukin-10 and the immune response against cancer:
a counterpoint
Simone Mocellin,*,1 Francesco M. Marincola,† and Howard A. Young‡
*Department of Oncological & Surgical Sciences, University of Padova, Italy; †Immunogenetics Laboratory,
Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland;
and ‡Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute,
Frederick, Maryland
Abstract: Although interleukin-10 (IL-10) is
commonly regarded as an anti-inflammatory, im-
munosuppressive cytokine that favors tumor es-
cape from immune surveillance, a wealth of evi-
dence is accumulating that IL-10 also possesses
some immunostimulating properties. In fact, IL-10
has the pleiotropic ability of influencing positively
and negatively the function of innate and adaptive
immunity in different experimental models, which
makes it questionable to merely categorize this
cytokine as a target of anti-immune escape thera-
peutic strategies or rather, as an immunological
adjuvant in the fight against cancer. Here, we re-
view available data about the immunostimulating
anticancer properties of IL-10, and in particular,
we focus on the hypothesis that in contrast to what
occurs in secondary lymphoid organs, IL-10 over-
expression within the tumor microenvironment
may catalyze cancer immune rejection. J. Leukoc.
Biol. 78: 1043–1051; 2005.
Key Words: tumor-infiltrating macrophages 䡠 natural killer cell
䡠 tumor-associated antigen 䡠 tumor immunology 䡠 cytokine
INTRODUCTION
Although the relationship between interleukin-10 (IL-10) and
cancer has been studied extensively, the ultimate role of IL-10
in tumor biology remains enigmatic. The significance of IL-10
production within the tumor microenvironment, which can be
sustained by malignant cells and tumor-infiltrating macro-
phages (TIM) and lymphocytes [including natural killer (NK)
and T cells], is debated [1, 2]. IL-10 can favor tumor growth in
vitro by stimulating cell proliferation and inhibiting cell apo-
ptosis [3, 4]. High systemic levels of IL-10 correlate with poor
survival of some cancer patients [5– 8]: however, this might
reflect just the bulk of disease, and also, no correlation is
reported [9, 10]. Moreover, opposite findings (higher IL-
103better survival) are observed when the cytokine levels are
assessed in tumor samples [11], and results from studies cor-
relating IL-10 polymorphism and cancer risk/prognosis are
controversial [6, 12, 13]. IL-10 can also inhibit tumor-induced
angiogenesis and enhance the production of tumor-toxic mol-
ecules [e.g., nitric oxide (NO)], which leads to tumor regression
0741-5400/05/0078-1043 © Society for Leukocyte Biology
in some preclinical models [14, 15]. Nevertheless, the most
controversial topic is the effect of this cytokine on the immune
response against cancer. As a result of its ability to inhibit
several key phenomena underlying an adaptive immune re-
sponse, several authors sustain the teleological hypothesis that
IL-10 is an immunosuppressive molecule secreted by tumors
(or tumor-infiltrating immune cells) to allow malignant cells to
escape from immune surveillance [16 –18]. By contrast, other
preclinical and clinical models suggest that IL-10 might favor
immune-mediated rejection of cancer. As an effective antican-
cer immune response is determined by a dynamic sequence of
coordinated events, including the timely intervention of innate
and adaptive immunity cell mediators, the role of IL-10 should
not be inferred from its effects on single immune cell types or
biological phenomena but rather considered within the frame of
a highly complex and still incompletely elucidated biological
puzzle.
In this review, we summarize the available data about the
relationship between IL-10 and anticancer immunity and hy-
pothesize that under some circumstances, this cytokine may
support an effective immune attack against malignant cells in
vivo, which questions the common belief that IL-10 only be-
haves as an immunosuppressive factor promoting tumor im-
mune escape.
IL-10 AND IMMUNE RESPONSE
A body of evidence has accumulated that IL-10 can have
pleiotropic effects on adaptive and innate immunity cell me-
diators. Although several studies (particularly in vitro) show
that IL-10 can actively mediate immune suppression, other
experimental models lead to quite opposite conclusions [19].
Helper and cytotoxic T cells
Because of its ability to reduce the production of IL-2 and
interferon- ␥ (IFN-␥) by murine and human T helper cell type
1 (Th1) lymphocytes, IL-10 was initially named a cytokine-
1
Correspondence: Department of Oncological & Surgical Sciences, Univer-
sity of Padova, Via Giustiniani, 2, 35128 Padova, Italy. E-mail: mocellins
@hotmail.com
Received July 4, 2005; revised August 3, 2005; accepted August 8, 2005;
doi: 10.1189/jlb.0705358.
Journal of Leukocyte Biology Volume 78, November 2005 1043
synthesis inhibitory factor [20]. This, together with the IL-10
property of stimulating B cell function, led to the classification
of IL-10 among Th2 cytokines with the physiological role to
terminate T cell-mediated immunity and start a humoral im-
mune response [21]. More recent studies have clarified that the
IL-10 immunosuppressive activity on T cells is mainly indirect
and is mediated by other two-immune cell types [dendritic
cells (DC) and T regulatory (Treg) cells], as discussed below. It
is interesting that whereas naive CD4⫹ T cells are targeted by
IL-10 (likely through the inhibition of the CD28 signaling
pathway), activated and memory T cells seem to be rather
refractory toward this cytokine, which might be related to the
down-regulation of IL-10 receptor (IL-10R) on T cell activation
[14, 22]. Furthermore, IL-10, which does not exert a direct
inhibitory effect on antigen-experienced CD8⫹ cytotoxic T
cells (CTL), under certain conditions, can even increase their
cytotoxic activity and/or proliferation rate [14, 20, 23–26].
DC
IL-10 can impair tumor-associated antigen (TAA) cross-pre-
sentation by DC, thus potentially preventing T cells from
mounting an effective immune response against malignant cells
[17]. IL-10 hinders the antigen-presenting properties of DC by
reducing their expression of human leukocyte antigen (HLA)
class II molecules, intercellular adhesion molecules (e.g.,
ICAM-1), costimulatory molecules (i.e., CD80/B7-1 and CD86/
B7.2), and Th1 cytokines (e.g. IL-12), which correlate with its
ability to impair primary, alloantigen-specific T cell responses
[14, 20]. Of note, as HLA class I expression on the surface of
DC is not down-regulated by IL-10 [27], cross-priming of CTL
might not be as much affected by this cytokine as is that of
CD4⫹ T cells [20]. These observations have been extended to
different experimental models and have shown that IL-10-
conditioned DC can induce a state of anergy in alloantigen- or
peptide-activated T cells [28 –30]. Like lymphocytes, DC can-
not only be a target for but also a source of IL-10 [31]: As
discussed below, it has been proposed that IL-10-producing
DC may be involved in the generation of Treg cells with defined
immunosuppressive functions. Although inhibition of DC-me-
diated antigen presentation is a well-documented result of
IL-10 administration, this cytokine also promotes antigen up-
take by DC [27, 32, 33] and inhibits their migration [34, 35].
Moreover, although IL-10 reduces the ability of murine DC to
respond to Toll-like receptor (TLR) ligands [31], in human
monocyte lineage cells, it increases the expression of TLR [36,
37], which might sensitize these cells to “danger” signal me-
diators [e.g., heat-shock proteins (hsp), double-stranded DNA,
TLR ligands] released in damaged tissues, including the tumor
microenvironment [38, 39]. Taken together, these consider-
ations support the hypothesis that IL-10 might play an impor-
tant role in an early phase of DC activity [27], when immature
DC must accumulate in the relevant arena (e.g., tumor micro-
environment), where they are loaded with antigens shed from
damaged tissues (e.g., TAA) and initiate the differentiation
process leading to the generation of fully active antigen-pre-
senting cells in secondary lymphoid organs (Fig. 1).
1044 Journal of Leukocyte Biology Volume 78, November 2005
Treg cells
CD4⫹ Treg cell subsets are major mediators of peripheral
immune tolerance through the regulation of Th1 and Th2
immune responses [41]. Treg cells contribute to the induction
of peripheral tolerance via expression of inhibitory cell-surface
molecules (CD4⫹/CD25⫹ T cells) or the production of immu-
noregulatory cytokines, such as IL-10 and transforming growth
factor-␤ {TGF-␤; type-1 Treg (Tr1) cells [42]}. Treg popula-
tions can be classified into naturally occurring Foxp3⫹/CD4⫹/
CD25⫹ Treg subset (CD4⫹CD25⫹ Treg) and antigen-driven
Treg producing IL-10 (IL-10-Treg) and TGF-␤ (TGF-␤-Treg),
which have been isolated under particular regimens of anti-
genic stimulation in vitro and in vivo [43]. The production and
action of these two cytokines are inter-related and likely in-
volve a positive feed-back loop, in which IL-10 enhances the
expression of TGF-␤ and vice versa. In fact, IL-10 enhances
the production of TGF-␤ and also controls the ability of target
cells to respond to TGF-␤. This involves the IL-10-mediated
restoration of the expression of TGF-␤ receptor 2 on recently
activated T cells, which usually down-regulate this receptor
and become insensitive to the inhibitory effects of TGF-␤ [44].
Conversely, TGF-␤ can promote the production of IL-10. These
two cytokines likely mediate Tr1 cell physiological function of
suppressing pathological immune responses (e.g. allergy, au-
toimmune disease), although Treg cells can also be involved in
the pathogenesis of certain diseases, as they can dampen the
reaction of the immune system to danger signals. It has been
proposed that IL-10 not only mediates Treg cell immunosup-
pressive activity but also plays a direct role in their genesis
[42]. In particular, the differentiation of Tr1 cells is likely
controlled by a subset of DC, which produces IL-10 and
expresses tolerogenic molecules (e.g., B7H1) [45– 47]. Regard-
ing cancer, IL-10 expression at early tumor sites promotes the
generation and activation of TGF-␤-Treg, which in turn, leads
to the systemic suppression of antitumor immunity in mice
[48]; moreover, the presence of Treg cells has been linked
recently to a worse prognosis in a large series of patients with
ovarian carcinoma [49].
Despite the above considerations, the ultimate effect of
IL-10 on the immunosuppressive activity of Treg cells in vivo
might not be as univocal as expected. Recent evidence sug-
gests that Treg cells are naturally resistant to TCR cross-
linking-induced apoptosis; however, administration of exoge-
nous IL-10 makes these T cells sensitive to apoptosis by
up-regulation of membrane-bound tumor necrosis factor (TNF)
and abolishes their suppressive function [50]. Accordingly, the
stimulatory effect of IL-10 on the generation/immunosuppres-
sive function of Treg cells might be counterbalanced by its
inhibitory effect on their survival. In addition, despite the
postulated role of Treg cells/IL-10 in shutting down the im-
mune response against established cancers, there is evidence
that Treg cells can prevent the development of tumors, espe-
cially through the production of IL-10. In fact, in animal
models of chronic inflammation, which represents a major risk
factor in the pathogenesis of several types of cancer [51], IL-10
produced by Treg cells inhibits the inflammatory response of
the host, ultimately opposing tumor development [52].
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Fig. 1. IL-10 and cancer. Besides its effects on angiogenesis and cell proliferation/apoptosis (left bottom), IL-10 can affect different aspects of anticancer
immunity. In secondary lymphoid organs, IL-10 inhibits the cross-presentation of TAA to T cells and favors the development of Treg cells with powerful
immunosuppressive functions. By contrast, high levels of IL-10 within the tumor microenvironment may favor immune-mediated tumor rejection by enhancing NK
cell activity (which in turn favors DC function) by increasing the TAA upload capability of DC and by enhancing cytotoxicity and migration of CTL. Overall, one
might hypothesize that IL-10 effects on the anticancer immune response can be different depending on the site of IL-10 production: In particular, although IL-10
overexpression within the tumor microenvironment might be beneficial for cancer immune rejection (increased innate immune response and likely primary immune
response), an IL-10-dominant cytokine profile in secondary lymphoid organs likely hinders the adaptive immune reaction toward TAA, thus compromising the
secondary immune response [40]. These considerations might have profound implications in the design of the next generation of anticancer immunotherapeutic
strategies. Solid lines, Molecular/cellular interactions; broken lines, cell migration; large arrows, secretory activity. ROS, Reactive oxygen species; PGE2:
prostaglandin E2; CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cellular cytotoxicity; STAT3, signal transducer and activator of
transcription 3; COX-2, cyclooxygenase-2; VEGF, vascular endothelial growth factor; b-FGF, basic fibroblast growth factor; HTL, helper T cell; TCR, T cell
receptor; CTLA-4, CTL antigen-4; IgM/G, immunoglobulin M/G.

NK cells and macrophages
Besides DC, other innate immunity cell mediators play a
significant role in the determinism of an effective immune
response. For instance, the early participation of NK cells in
the host reaction to pathogen/cancer invasion could influence
the subsequent development of an adaptive immune response,
perhaps providing cues to indicate a “nonself”/“dangerous”
encounter. Furthermore, an aberrant innate reaction to self-
tissue might promote an autoimmune disease, as demonstrated
by the fact that NK cells are required for the development of
experimental autoimmune myasthenia gravis in mice [53]. In
addition to a direct cytotoxic effect toward malignant cells, NK
cells efficiently collaborate with DC to mount an effective
adaptive immune response toward different types of noxa pa-
togena [54, 55], including cancer [56].
Although IL-10 inhibits IFN-␥ and TNF production by NK
cells in vitro [20], it also promotes NK cell cytotoxicity in
preclinical models [57, 58]. Moreover, malignant cells exposed
to IL-10 down-regulate HLA class I molecules on their surface
[59], which reduces their sensitivity to CTL but increases that
to NK cell cytotoxicity [60].
These observations support the hypothesis that at an early
stage of the immune response, IL-10 might induce lysis of
diseased (e.g., malignant) cells by stimulating the innate arm of
the immune system, which in turn, would lead to secondary,
beneficial effects on the incoming adaptive immune response
[56]. In fact, NK cell-mediated cytolysis of target cells would
provide DC with adequate amounts of relevant antigens (e.g.,
TAA), chemotactic peptides [61], and danger signal molecules,
which ultimately initialize the process of DC maturation [62,
63]. Upon addition of a Th1 stimulus (e.g., IL-2, IL-12) in
secondary lymphatic organs (e.g., lymph nodes), the balance
would then be shifted toward full maturation of DC, with
consequent production of costimulatory molecules and cyto-
kines with proliferative/activating effects on naı̈ve T cells
(Fig. 1).
Unlike NK cells, other innate immunity mediators might
hinder tumor immune rejection. For instance, ROS produced

Mocellin et al. IL-10 and anticancer immunity 1045

by TIM have been described to inhibit NK cell activity [64],
and the inhibition of ROS production by histamine adminis-
tration improves the results of immunotherapy in patients with
metastatic melanoma [65]. Other macrophage- or tumor-de-
rived molecules such as NO and PGs (e.g., PGE2) are believed
to inhibit innate and ultimately, adaptive immunity, thus fa-
voring tumor escape from immune surveillance [66, 67]. As
IL-10 can decrease the production of such immunosuppressive
molecules [68 –73], a novel molecular mechanism underlying
the observed immunostimulating properties of this cytokine is
suggested.
CANCER MODELS OF IL-10-MEDIATED
IMMUNOSUPPRESSION
Several preclinical models support the hypothesis that IL-10
might blunt the immune response against cancer. IL-10 can act
as a negative mediator in the cross-talk between innate and
adaptive antitumor immunity: For instance, investigators have
reported that TCR-␥␦-bearing T cells and TCR-␣␤ intermedi-
ate T cells suppress NK and NKT cells by elaborating IL-10
and TGF-␤, which ultimately, leads to impaired activation of
CTL, Th1 CD4⫹ T cells, and tumor immune privilege [74]. In
vitro, IL-10 pretreatment can convert different types of tumor
cells (e.g., melanoma, lymphoma) to a CTL-resistant phenotype
by decreasing the expression of HLA class I molecules on their
surface [60, 75]. Similarly, IL-10 production by human basal
and squamous cell carcinoma prevents in vitro lysis of autol-
ogous malignant cells by tumor-infiltrating lymphocytes [76].
This effect is likely mediated by reduced expression of the
so-called transporter associated with antigen processing-1 and
-2, which in vitro, leads to reduced translocation of peptides to
the endoplasmic reticulum and therefore, in diminished HLA
class I/peptide complex loading and cell-surface levels [60,
75]. Moreover, IL-10 expression by tumor cells has been
associated with increased expression of the nonclassical HLA
class Ib molecule (HLA-G), which may inhibit the cytolytic
activity of NK cells and CTL [77].
In vitro, CD8⫹ T cells can be anergized toward melanoma-
associated antigens when stimulated with IL-10-conditioned
DC [78], and DC, which infiltrate progressing melanoma me-
tastases in humans, are characterized by low expression of
CD86 and IL-12 but enhanced capacity to produce IL-10 [79].
Yet, a Lewis lung carcinoma cell line grows more rapidly in a
transgenic mouse expressing IL-10 under control of an IL-2
promoter than in nontransgenic control mice [80], supposedly
by suppressing DC function [81]. Moreover, IL-10-producing
monocytes, which inhibit T cell proliferation, have been iso-
lated from the ascites of patients with ovarian carcinoma [82].
CTLA-4 is critical in several experimental settings, where its
blockade promotes antitumor immunity [83]. In a mouse model
of plasmacytoma, it has been demonstrated that a large part of
the immunosuppressive effects of CTLA-4 can be attributed to
IL-10: In fact, inhibition of IFN-␥ secretion induced by
CTLA-4 is blocked using an anti-IL-10 antibody, and in vivo
treatments with anti-CTLA-4 and anti-IL-10 antibody are
equally effective in inducing tumor responses without any
addictive effect [84]. Other investigators have also shown that
1046 Journal of Leukocyte Biology Volume 78, November 2005
the immunosuppressive effects of COX-2, overexpressed by
some tumor cells, at least in part, depend on IL-10 up-regu-
lation [85– 87]; nevertheless, opposite findings have been also
reported [88].
It is important that inhibition of IL-10 production by T cells
or malignant cells using low-dose cyclophosphamide [89], anti-
IL-10/IL-10R-blocking antibodies [84, 90], or anti-IL-10 an-
tisense oligonucleotides [91] improves cancer-specific immune
responses in some preclinical tumor models, which led the
authors to advocate the use of IL-10-neutralizing agents as
immunological adjuvants in the design of anticancer vaccines.
CANCER MODELS OF IL-10 MEDIATED
IMMUNOSTIMULATION
A large body of preclinical evidence is in contrast with the
above-mentioned reports. IL-10 has been associated with tu-
mor regression in different settings, although the molecular
mechanisms underlying this effect have not been well charac-
terized yet (Table 1). Transfection of mouse carcinoma [92,
93] and melanoma [94] cell lines with IL-10 elicits loss of
tumorigenicity and increases immunogenicity accompanied by
a strong lymphocyte and antibody-dependent immune memory.
Other investigators not only have reported that IL-10-secreting
murine tumor cells can be highly immunogenic as compared
with unmodified parental cells but also have shown that IL-10
does not inhibit IFN-␥ production by CD8⫹ cytotoxic T cells,
opposite to what is observed with CD4⫹ Th1 cells [95]. Yet,
exogenous IL-10 administration can mediate regression of es-
tablished melanoma and breast cancer metastases in various
preclinical in vivo models [96 –100]. It is noticeable that tumor
rejection is inhibited by viral IL-10, and eukaryote cellular
IL-10 (cIL-10) favors the eradication of cancer cells, confirm-
ing that the double function of this cytokine can be split and
linked to different domains of the molecule [101]. In particular,
investigators have shown that a single amino acid substitution
can abrogate the ability of cIL-10 to mediate tumor regression
[102].
Using scid models, some authors have linked the IL-10
antitumor effect to enhanced NK cell activity [97, 99], and
others
⫹
have demonstrated that it depends on CD8⫹ [103] or
CD4 [104] T cell function. By positively affecting the antican-
cer function of innate and/or adaptive immunity mediators,
IL-10 might boost the immune reaction to malignant cells, at
least under some circumstances. It has been shown that ad-
ministration of IL-10 before anticancer vaccination results in
immune suppression and tumor progression, in line with the
well-known IL-10 inhibitory activity on DC-mediated antigen
presentation [103]. However, injection of IL-10 just after im-
munization significantly enhances antitumor immunity and
vaccine efficacy. In addition, the number of antigen-specific
CTLs is higher in animals treated with vaccine/IL-10 rather
than in those with vaccine alone, which led investigators to
suggest that IL-10 might act as an immunological adjuvant
maintaining the number of antigen-experienced CTL during
vaccine-induced tumor rejection.
Literature reports on in vivo findings in humans are scarce.
Investigators have described the cytokine profile of lympho-
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 TABLE 1. Immune-Related Molecules Modulated by IL-10 at Gene and/or Protein Level and Their Potential Role
in IL-10-Mediated Immunostimulation

Molecular target Target function Immunological effect

1 TIA-1 1 NK cell cytotoxicity 1 NK cell antitumor activity

1 cathepsin
1 granzyme-A 1 CTL and NK cell cytotoxicity 1 NK cells and CTL antitumor activity
1 CXCL7 1 leukocyte chemotaxis & migration 1 tumor infiltration by leukocytes
1 CCL6
1 CCL3
(MIP1␣)
1 FPR
1 PAFR
1 HSP70 1 dendritic cell activity 1 TAA upload
1 TLR
1 CD30 ligand 1 lymphocyte survival 1 lymphocyte antitumor activity
1 FLIP
2 HLA class I 1 sensitivity to NK cell activity 1 NK cell antitumor activity
2 JNK 1 ROS production 2 immunosuppression mediated by ROS, nitric oxide, and prostaglandins
2 SOCS3 1 nitric oxide synthase expression
2 COX 1 prostaglandin synthesis

TIA-1, Cytotoxic granule-associated protein; CXCL7, CXC chemokine ligand 7; CCL6, CC chemokine ligand 6; MIP1␣, macrophage-inflammatory protein-1␣;
FPR, formyl-peptide receptor; PAFR, platelet-activating factor; FLIP, Fas-associated death domain-like IL-1␤-converting enzyme (caspase-8) inhibitory protein;
JNK, c-Jun-activated protein kinase; SOCS3, suppressor of cytokine signaling-3.

cytes harvested from the lymph nodes draining the vaccination
site of patients with renal cell carcinoma treated with irradiated
autologous tumor cells: In these lymphocytes, the IFN-␥/IL-10
ratio was higher in responding rather than in nonresponding
patients [105]. By contrast, tumor regression following active,
specific immunotherapy with an allogeneic antimelanoma vac-
cine preparation is associated with high IL-10 production by
peripheral blood mononuclear cells [106]. In patients under-
going vaccination with TAA-derived peptides plus IL-2, we
have analyzed the immune-related gene profile of in-transit
melanoma metastases [58, 107]. In pretreatment samples,
IL-10 results overexpressed in responding versus progressing
lesions. A follow-up study about an independent patient pop-
ulation has confirmed this finding by identifying a positive
correlation between clinical regression and IL-10 protein lev-
els in tumor cells from samples obtained before therapy [1].
Consequently, one might speculate that the presence of high in
situ levels of IL-10 might precondition the tumor microenvi-
ronment to the anticancer effects of systemic vaccination. As
TIA-1, a gene encoding a cytotoxicity-related protein, is also
overexpressed in responding metastases, and IL-10 increases
TIA-1 expression specifically by NK cells, these findings sup-
port the hypothesis that IL-10 might exert a permissive activity
on vaccine-induced adaptive immunity by increasing NK cell
antitumor function [108] (Fig. 1).
DISCUSSION AND CONCLUDING REMARKS
Although several tumor immunologists continue to consider
IL-10 an immunosuppressive cytokine tout court, the complex
relationship between this molecule and cancer is still incom-
pletely elucidated. The intrinsically pleiotropic biological ac-
tivity of IL-10 and the variability of cancer models (e.g.,
human/animal, in vitro/in vivo, systemic/local IL-10 overpro-
duction/administration, solid/hematological malignancies)
used to address the issue of the ultimate role of IL-10 in tumor
immunology are likely responsible for the controversial find-
ings reported in the literature and summarized above. The
difficulty of interpreting experimental data is well illustrated in
experiments, where tumors have been transplanted in trans-
genic mice in which DC overproduce IL-10: Although the
tumors initially grow faster than in control mice, eventually
they are rejected [109]. Moreover, in contrast to results from
preclinical models, intravenous administration of recombinant
IL-10 to humans produces proinflammatory effects by enhanc-
ing release of IFN-␥, IFN-inducible protein 10, TNF, and IL-1
and appears to induce activation of CTL and NK cells, as
reflected by increased plasma levels of granzyme-B [110, 111].
Finally, the task of classifying IL-10 as an immunosuppressive
or an immunostimulating cytokine is particularly challenging,
taking into consideration that in vivo, this molecule can influ-
ence cancer growth/progression by affecting nonimmune-re-
lated phenomena, such as angiogenesis and malignant cell
proliferation/apoptosis [2]. This is why even IL-10 knockout
models have yielded opposite results, depending on the exper-
imental settings: For instance, in IL-10-deficient mice, B cell
tumors (which are highly sensitive to the proliferative effect of
IL-10) grow more slowly [112], whereas inflammation-based
bowel cancerogenesis (which is hindered by IL-10) is reduced
significantly [113]. In addition, when the antitumor immune
response of IL-10⫺/⫺ tumor-bearing animals was investi-
gated, conflicting findings have been reported [104, 114].
Although no definitive conclusion can be drawn currently as
to whether IL-10 should be considered a potential immunolog-
ical adjuvant or rather, a mediator of tumor immune escape,
available data appear to tip the balance toward the hypothesis
that IL-10 might contribute to the immune-mediated rejection
of cancer, at least under some circumstances.

Mocellin et al. IL-10 and anticancer immunity 1047

 The occurrence of mixed responses (regressing lesions con-
comitant with stable/progressing lesions) in the same patient
following different types of immunotherapeutic manipulation
and independently of a detectable tumor-specific immune re-
sponse in the peripheral blood [108, 115, 116] shows that a
conducive microenvironment is necessary for cancer immune
rejection to take place. In our above-mentioned experience
with vaccination of patients with metastatic melanoma, it was
evident that in situ IL-10 overexpression could not determine
cancer regression by itself, as the tumor was progressing before
vaccination [115]. Nevertheless, IL-10 might catalyze a suc-
cessful immune reaction to the therapeutic vaccination by
three main mechanisms: i) IL-10 can stimulate the anticancer
activity of intratumoral innate immune effectors, such as NK
cells, which in turn might positively affect the adaptive im-
mune response by favoring the activity of DC. Then, systemic
immunization (i.e., anticancer vaccination), which mainly acts
in the secondary lymphoid organs (e.g., lymph nodes), would
increase the frequency of tumor-specific T cells up to the
therapeutically critical number. Furthermore, there is a need
for a continuous supply of TAA to secondary lymphatic organs
to maintain an effective adaptive immune response [117], and
IL-10 could increase such TAA availability by stimulating NK
cell-mediated tumor cytolysis. ii) High levels of intratumoral
IL-10 can recruit antigen-experienced CTL into the relevant
arena. In fact, leukocyte recruitment is enhanced by IL-10 via
chemotaxis [118 –120] and induction of endothelial cell adhe-
sion molecule expression [121–123]. Also, in this case, a
differential effect on T cell subsets has been reported— only
CD8⫹ T cell migration being increased by IL-10 [118, 124]. iii)
IL-10 can directly stimulate/maintain the cytotoxic activity of
CTL present in the tumor microenvironment [103], which
counteracts the phenomenon of local, functional tolerance of
tumor-specific CTL [125]; this would also make IL-10 an
important mediator of the effector phase of the adaptive im-
mune response against cancer.
Some recent findings strengthen the idea that peripheral
tolerance toward cancer should be fought from within the tumor
microenvironment, indirectly supporting the theory that the
above-mentioned IL-10 immunostimulating properties might
be of clinical value in cancer immunotherapy. For instance,
some investigators have reported that breaking the barrier
comprised of nonantigenic stromal cells by forcing the expres-
sion of proinflammatory/chemotactic factors within the tumor
tissue can, by itself, reverse immune tolerance, evoke a tumor-
specific, adaptive immune response, and lead to the eradica-
tion of established cancers [126 –128].
Finally, as most TAA are self-antigens, and anticancer vac-
cination can be seen as a therapeutic attempt to induce an
autoimmune response against cancer [129], milestone autoim-
munity experiments can provide further (although indirect)
evidence supporting our hypothesis. In the nonobese diabetic
mouse model, insulin-dependent diabetes spontaneously fol-
lows the destruction of pancreatic islet ␤ cells mediated by
CD4⫹ and CD8⫹ T cells [19]. Systemic administration of IL-10
is followed by protection from diabetes, which is likely a result
of its inhibitory effects on DC (and thus, on adaptive immune
response) in secondary lymphoid organs [20, 130]. By contrast,
IL-10 local production by transgenic, pancreatic ␤ cells accel-
1048 Journal of Leukocyte Biology Volume 78, November 2005
erates the onset of diabetes in mice, which strengthens the idea
that local overexpression of IL-10 might contribute to break the
physiological immune tolerance to self-antigens (including
TAA), ultimately leading to the destruction of the target tissue.
Overall, if this hypothesis were validated by further evi-
dence (particularly in humans), a new avenue in the design of
T cell-directed anticancer vaccines would be opened, in which
a timely and effective stimulation of innate and adaptive im-
mune response might be achieved by increasing IL-10 levels
within the tumor microenvironment. To this aim, the model of
limb-sited tumors (e.g., in transit melanoma metastases, limb
soft-tissue sarcomas) appears to be particularly suitable for
human experimentation, as it allows for the administration of
IL-10 or IL-10 vectors (e.g., IL-10-coding viruses or plasmids)
by means of isolated limb perfusion [131], which would enable
investigators to test the immunomodulatory activity of the
cytokine without incurring its potential systemic toxicity.
ACKNOWLEDGMENT
Apologies are made to those authors whose work on IL-10 has
not been cited as a result of length considerations.
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