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Originally published online as doi:10.1189/jlb.0705358 on October 4, 2005

Published online before print October 4, 2005
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(Journal of Leukocyte Biology. 2005;78:1043-1051.)
© 2005 by Society for Leukocyte Biology

Interleukin-10 and the immune response against cancer: a counterpoint

Simone Mocellin*,1, Francesco M. Marincola{dagger} and Howard A. Young{ddagger}

* Department of Oncological & Surgical Sciences, University of Padova, Italy;
{dagger} Immunogenetics Laboratory, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
{ddagger} Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland

1Correspondence: Department of Oncological & Surgical Sciences, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. E-mail: mocellins{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 IL-10 AND IMMUNE RESPONSE
 CANCER MODELS OF IL-10-MEDIATED...
 CANCER MODELS OF IL-10...
 DISCUSSION AND CONCLUDING...
 REFERENCES
 
Although interleukin-10 (IL-10) is commonly regarded as an anti-inflammatory, immunosuppressive cytokine that favors tumor escape from immune surveillance, a wealth of evidence 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 therapeutic strategies or rather, as an immunological adjuvant in the fight against cancer. Here, we review 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 overexpression within the tumor microenvironment may catalyze cancer immune rejection.

Key Words: tumor-infiltrating macrophages • natural killer cell • tumor-associated antigen • tumor immunology • cytokine


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
IL-10 AND IMMUNE RESPONSE
 CANCER MODELS OF IL-10-MEDIATED...
 CANCER MODELS OF IL-10...
 DISCUSSION AND CONCLUDING...
 REFERENCES
 
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 macrophages (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 apoptosis [3 , 4 ]. High systemic levels of IL-10 correlate with poor survival of some cancer patients [5 6 7 8 ]: however, this might reflect just the bulk of disease, and also, no correlation is reported [9 , 10 ]. Moreover, opposite findings (higher IL-10->better survival) are observed when the cytokine levels are assessed in tumor samples [11 ], and results from studies correlating 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 molecules [e.g., nitric oxide (NO)], which leads to tumor regression 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 response, 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 17 18 ]. By contrast, other preclinical and clinical models suggest that IL-10 might favor immune-mediated rejection of cancer. As an effective anticancer 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 hypothesize 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 behaves as an immunosuppressive factor promoting tumor immune escape.


   IL-10 AND IMMUNE RESPONSE
TOP
 ABSTRACT
 INTRODUCTION
 IL-10 AND IMMUNE RESPONSE
CANCER MODELS OF IL-10-MEDIATED...
 CANCER MODELS OF IL-10...
 DISCUSSION AND CONCLUDING...
 REFERENCES
 
A body of evidence has accumulated that IL-10 can have pleiotropic effects on adaptive and innate immunity cell mediators. 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- {gamma} (IFN-{gamma}) by murine and human T helper cell type 1 (Th1) lymphocytes, IL-10 was initially named a cytokine-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 immune 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 24 25 26 ].

DC
IL-10 can impair tumor-associated antigen (TAA) cross-presentation 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 29 30 ]. Like lymphocytes, DC cannot 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-mediated antigen presentation is a well-documented result of IL-10 administration, this cytokine also promotes antigen uptake 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 mediators [e.g., heat-shock proteins (hsp), double-stranded DNA, TLR ligands] released in damaged tissues, including the tumor microenvironment [38 , 39 ]. Taken together, these considerations support the hypothesis that IL-10 might play an important role in an early phase of DC activity [27 ], when immature DC must accumulate in the relevant arena (e.g., tumor microenvironment), 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-presenting cells in secondary lymphoid organs (Fig. 1 ).



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  		Figure 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.

 
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 immunoregulatory cytokines, such as IL-10 and transforming growth factor-ß {TGF-ß; type-1 Treg (Tr1) cells [42 ]}. Treg populations 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-ß (TGF-ß-Treg), which have been isolated under particular regimens of antigenic stimulation in vitro and in vivo [43 ]. The production and action of these two cytokines are inter-related and likely involve a positive feed-back loop, in which IL-10 enhances the expression of TGF-ß and vice versa. In fact, IL-10 enhances the production of TGF-ß and also controls the ability of target cells to respond to TGF-ß. This involves the IL-10-mediated restoration of the expression of TGF-ß receptor 2 on recently activated T cells, which usually down-regulate this receptor and become insensitive to the inhibitory effects of TGF-ß [44 ]. Conversely, TGF-ß can promote the production of IL-10. These two cytokines likely mediate Tr1 cell physiological function of suppressing pathological immune responses (e.g. allergy, autoimmune 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 immunosuppressive 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 46 47 ]. Regarding cancer, IL-10 expression at early tumor sites promotes the generation and activation of TGF-ß-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 suggests that Treg cells are naturally resistant to TCR cross-linking-induced apoptosis; however, administration of exogenous 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/immunosuppressive 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 immune response against established cancers, there is evidence that Treg cells can prevent the development of tumors, especially 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 ].

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 patogena [54 , 55 ], including cancer [56 ].

Although IL-10 inhibits IFN-{gamma} 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 cytokines with proliferative/activating effects on naïve T cells (Fig. 1) .

Unlike NK cells, other innate immunity mediators might hinder tumor immune rejection. For instance, ROS produced by TIM have been described to inhibit NK cell activity [64 ], and the inhibition of ROS production by histamine administration improves the results of immunotherapy in patients with metastatic melanoma [65 ]. Other macrophage- or tumor-derived molecules such as NO and PGs (e.g., PGE2) are believed to inhibit innate and ultimately, adaptive immunity, thus favoring tumor escape from immune surveillance [66 , 67 ]. As IL-10 can decrease the production of such immunosuppressive molecules [68 69 70 71 72 73 ], a novel molecular mechanism underlying the observed immunostimulating properties of this cytokine is suggested.


   CANCER MODELS OF IL-10-MEDIATED IMMUNOSUPPRESSION
TOP
 ABSTRACT
 INTRODUCTION
 IL-10 AND IMMUNE RESPONSE
 CANCER MODELS OF IL-10-MEDIATED...
CANCER MODELS OF IL-10...
 DISCUSSION AND CONCLUDING...
 REFERENCES
 
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-{gamma}{delta}-bearing T cells and TCR-{alpha}ß intermediate T cells suppress NK and NKT cells by elaborating IL-10 and TGF-ß, 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 autologous 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 metastases 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 isolated 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-{gamma} 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 the immunosuppressive effects of COX-2, overexpressed by some tumor cells, at least in part, depend on IL-10 up-regulation [85 86 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 antisense 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
TOP
 ABSTRACT
 INTRODUCTION
 IL-10 AND IMMUNE RESPONSE
 CANCER MODELS OF IL-10-MEDIATED...
 CANCER MODELS OF IL-10...
DISCUSSION AND CONCLUDING...
 REFERENCES
 
A large body of preclinical evidence is in contrast with the above-mentioned reports. IL-10 has been associated with tumor regression in different settings, although the molecular mechanisms underlying this effect have not been well characterized 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-{gamma} 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 established melanoma and breast cancer metastases in various preclinical in vivo models [96 97 98 99 100 ]. 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, confirming 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 ].


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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

 
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 anticancer 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 administration 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 immunization 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 lymphocytes 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-{gamma}/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 vaccine preparation is associated with high IL-10 production by peripheral blood mononuclear cells [106 ]. In patients undergoing 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 population has confirmed this finding by identifying a positive correlation between clinical regression and IL-10 protein levels 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 microenvironment 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 support 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
TOP
 ABSTRACT
 INTRODUCTION
 IL-10 AND IMMUNE RESPONSE
 CANCER MODELS OF IL-10-MEDIATED...
 CANCER MODELS OF IL-10...
 DISCUSSION AND CONCLUDING...
REFERENCES
 
Although several tumor immunologists continue to consider IL-10 an immunosuppressive cytokine tout court, the complex relationship between this molecule and cancer is still incompletely elucidated. The intrinsically pleiotropic biological activity of IL-10 and the variability of cancer models (e.g., human/animal, in vitro/in vivo, systemic/local IL-10 overproduction/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 findings reported in the literature and summarized above. The difficulty of interpreting experimental data is well illustrated in experiments, where tumors have been transplanted in transgenic 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 enhancing release of IFN-{gamma}, 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 influence cancer growth/progression by affecting nonimmune-related 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 experimental 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 investigated, 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 immunological 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.

The occurrence of mixed responses (regressing lesions concomitant with stable/progressing lesions) in the same patient following different types of immunotherapeutic manipulation and independently of a detectable tumor-specific immune response 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 successful 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 immune 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 [118 119 120 ] and induction of endothelial cell adhesion molecule expression [121 122 123 ]. 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 immune 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 expression 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 eradication of established cancers [126 127 128 ].

Finally, as most TAA are self-antigens, and anticancer vaccination can be seen as a therapeutic attempt to induce an autoimmune response against cancer [129 ], milestone autoimmunity experiments can provide further (although indirect) evidence supporting our hypothesis. In the nonobese diabetic mouse model, insulin-dependent diabetes spontaneously follows the destruction of pancreatic islet ß 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 ß cells accelerates 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 evidence (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 immune 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.


   ACKNOWLEDGEMENTS
 
Apologies are made to those authors whose work on IL-10 has not been cited as a result of length considerations.

Received July 4, 2005; revised August 3, 2005; accepted August 8, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 IL-10 AND IMMUNE RESPONSE
 CANCER MODELS OF IL-10-MEDIATED...
 CANCER MODELS OF IL-10...
 DISCUSSION AND CONCLUDING...
 REFERENCES
 

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