IL10 and Cancer

There are a number of reports describing elevated levels of IL-10 expression in patients with particular cancers, including malignant melanoma,16-19 ovarian cancer20 and other carcinomas,21-24 lymphoma and myeloma.25,26 These elevated levels have been reported both in the serum and/or tumor lesions. Furthermore, a negative correlation between circulating levels of IL-10 and prognosis has been reported in patients with solid tumors, including lung cancer,22 renal carcinoma24 and gastrointestinal tumors27 and hematological malignancies.2 -29 A simplistic interpretation of these data would be that elevated IL-10 levels are associated with suppression of anti-tumor immune responses. However, elevated IL-10 expression can occur for a number of reasons. Production by tumor and other cells may indeed result in suppression of anti-tumor immune responses, but IL-10 may also act as a tumor growth factor, as evidenced by the action of exogenous IL-10 on human melanoma cells lines.30 In addition, IL-10 can also be produced by activated cells involved in anti-tumor immune responses and so may be indicative of a potent anti-tumor immune response. Indeed, it should be noted that elevated IL-10 levels do not correlate with prognosis in all studies31 and in some cases favorable prognosis has been associated with elevated IL-10 expression.32

More convincing data come from studies of IL-10 gene therapy in animal models of tumor growth and establishment, which consistently demonstrate an anti-tumor role for IL-10. In a colon carcinoma mouse model, transfection of tumor cells with IL-10 reduces the malignant potential of the tumor cells and induces a predominant Th2-mediated tumor rejection re-sponse.33 Similarly, IL-10 transfected cell lines derived from mouse mammary adenocarcinoma,34 ovarian carcinoma,35 malignant melanoma,36 Burkitt's lymphoma,37,38 prostate39 and colon cancers33 show significant inhibition of tumor growth. In support of this, systemic administration of IL-10 has inhibited tumor metastasis in various murine models, including melanomas,14,40 sarcomas and colorectal carcinomas.40

The mechanisms behind these antitumor effects are still incompletely understood. Many researchers attribute the antitumor effects of IL-10 to its effects on NK cell activation,14,15 although actions on T cells,40 macrophages41 and nitric oxide42 have also been implicated. In addition, IL-10 enhances the susceptibility of target cells to NK cell lysis by reducing cell surface MHC expression.43,44 However, an increasing body of evidence suggests that IL-10 exerts an antitumor effect by inhibition of angiogenesis. For example, in vitro studies of prostate tumor cells show that IL-10 stimulates tissue inhibitors of metalloproteinases (TIMPs) and inhibits matrix metalloproteinase (MMP) expression, so affecting induction of angiogenesis.45,46 Similarly, IL-10 gene transfection studies in malignant melanoma have shown that inhibition of tumor growth by inhibition of angiogenesis is accompanied by downregulation of synthesis of vascular endothelial growth factor (VEGF)—one of the most potent angiogenic factors—along with IL-1 p, tumor necrosis factor-a (TNFa), IL-6 and MMP-9 (all known to have angiogenic properties) in tumor-associated macrophages.17 In addition, in Burkitt's lymphoma, a lymphoid malignancy, introduction of human or viral IL-10 genes into tumors in SCID mice revealed an inhibition of VEGF-induced neovascularisation of the tumors.37

Accordingly, while the mechanisms remain unclear, there is a considerable and growing body of evidence for the antitumor properties of IL-10 and this may result at least in part from inhibition of angiogenesis, possibly by inhibition of production of angiogenic cytokines, growth factors and MMPs and stimulation of production of inhibitors of angiogenesis. Based on this, several investigators have suggested therapeutic use of IL-10 in cancer patientS'14'15'17'40'47 but at present no clinical trials have been performed.

An alternative strategy to determine the role of IL-10 in the development of particular malignancies is via genetic approaches. In recent years a considerable number of genetic polymorphisms have been identified within the IL-10 gene, particularly within the promoter region of the gene. Certain of these polymorphisms have been shown to be associated with differential levels of IL-10 expression. A considerable number of studies have been performed to determine whether IL-10 polymorphisms are associated with susceptibility to a large number of immune-mediated diseases (reviewed in refs. 48 and 49) and a small number of investigations have been performed in solid tumors and hematological malignancies and this literature is briefly reviewed below.

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