A cytokine-mediated link between innate immunity, inflammation, and cancer (original) (raw)

Another cytokine that activates STAT3 is IL-10 (Figure 2) (57). However, the effects of IL-10 are dramatically opposed to those of IL-6, as IL-10 is immunosuppressive and antiinflammatory (88). IL-10 inhibits NF-κB activation through ill-defined mechanisms (89, 90) and consequently inhibits the production of proinflammatory cytokines, including TNF-α, IL-6, and IL-12 (91). Given this, it is no wonder that IL-10 inhibits tumor development and progression (Figure 3). The most striking effects of IL-10 are seen in _Il10_–/– mice, which are more prone to colonic inflammation and CAC when chronically infected with certain enteric bacteria, such as Helicobacter hepaticus (92, 93). When newborn _Il10_–/– mice were treated with exogenous IL-10, they failed to develop any signs of intestinal inflammation or CAC (92).

Recent studies emphasize an essential link between IL-10–dependent antitumor activity and CD4+CD25+ Tregs (Figure 3) (94–97). In mice lacking RAG2, which lack functional lymphocytes, infection with H. hepaticus leads to colonic inflammation and adenocarcinoma, whereas infection of wild-type mice does not lead to these pathologies, suggesting that lymphocytes are required for preventing colonic inflammation (94). Accordingly, adoptive transfer of wild-type Tregs into _Rag2_–/– hosts prevents _H. hepaticus_–induced colon cancer (94, 95). A similar adoptive transfer of Tregs from _H. hepaticus_–free _Il10_–/– mice into _Rag2_–/– hosts demonstrated that IL-10 released by Tregs is needed for maintaining homeostasis of mucosal immune responses and for inhibition of IBD, dysplasia, and colon cancer (95, 96).

The IL-10–mediated antitumor activity of Tregs has also been observed in _Apc_Min/+ mice, which have a germline multiple intestinal neoplasia (Min) mutation in one of their adenomatosis polyposis coli tumor suppressor genes and therefore develop intestinal adenomas (97). Transfer of wild-type Tregs into _Apc_Min/+ mice prevents the development of adenomas and induces the rapid regression of established tumors, whereas transfer of _Il10_–/– Tregs fails to exert such effects (97). Decreased TNF-α and IFN-γ expression in mice receiving wild-type Tregs was also noticed (97). Glioma-specific CD4+ T cells have also been shown to require IL-10 for antitumor activity (98), and in xenograft studies, expression of IL-10 in melanoma or mammary or ovarian carcinomas resulted in antitumor effects (99, 100).

The mechanisms responsible for IL-10 inhibition of colitis are not completely clear but might be linked to its ability to counteract IL-12–driven inflammation (95, 101) or its ability to inhibit NF-κB activation (Figure 3) (89, 90). Indeed, enhanced IL-12p40 production by immune cells is a key feature of colonic inflammation in _Il10_–/– mice (101), and absence of IL-10–induced STAT3 activation was suggested to enhance NF-κB recruitment to the Il12p40 promoter (90). Suppression of TNF-α and IL-12 release by DCs and macrophages might also contribute to the antitumor activity of Tregs and IL-10 (102). However, it is not clear how STAT3 activation by IL-10 results in an antitumor effect, whereas STAT3 activation by IL-6 is considered to be pro-tumorigenic. More recent studies also suggest that IL-10 possesses immunostimulatory activity that enhances antitumor immunity (103, 104).

IL-10 has also been shown to modulate apoptosis and suppress angiogenesis during tumor regression (105, 106). Expression of IL-10 in mammary and ovarian carcinoma xenografts inhibits tumor growth and spread (100, 105). One mechanism by which IL-10 inhibits tumor growth was suggested to depend on downregulation of MHC class I expression, leading to enhanced NK cell–mediated tumor cell lysis (105). Inhibition of the tumor stroma was suggested to contribute to the antiangiogenic activity of IL-10 (106). The ability of IL-10 to downregulate VEGF, TNF-α, and IL-6 production by TAMs might also account for its inhibitory effect on the tumor stroma (99).

Although IL-10 usually exerts antitumor activity, its biological effects are not all that simple, and consistent with its ability to activate STAT3, it might also promote tumor development (Figure 2). Direct effects of IL-10 on tumor cells that might favor tumor growth have been reported. For example, an IL-10 autocrine and/or paracrine loop might have an important role in tumor cell proliferation and survival (107). The basis for this effect is primarily STAT3 activation, leading to upregulation of antiapoptotic genes such as BCL-2 or BCL-XL (107, 108). In addition, expression of IL-10 by tumor cells and TAMs is thought to promote the development of Burkitt lymphoma through the production of the TNF family member BAFF, which promotes B cell and lymphoma survival (109). An elevated amount of IL-10 in the plasma has been correlated with poor prognosis in diffuse large B cell lymphoma patients (110). A role for IL-10 in the progression of B cell malignancies is also seen in _Il10_–/– mice, in which B cell tumors grow more slowly (111). In a B16-melanoma xenograft model, IL-10–transfected cancer cells form more vascularized tumors and exhibit further growth (112). In addition to direct growth modulation of cancer cells, the ability of IL-10 to suppress adaptive immune responses has also been suggested to favor tumor escape from immune surveillance (104).

In summary, IL-10 has complex effects on tumor development. In many experimental systems, IL-10 is found to exert antitumor activity, but in other cases it can be pro-tumorigenic. These dramatically opposing effects of IL-10 might depend on interactions with either cytokines or factors found in the tumor microenvironment, as it is unlikely that IL-10 functions in isolation. A better understanding of IL-10 signaling is needed before its effects on tumor growth and antitumor immunity can be fully explained.