in cancer therapy, however, is hindered by severe toxic side effects, primarily because of the extremely high levels of IFN-γ that it induces (82).
Although IL-23 can enhance the proliferation of memory T cells and the production of IFN-γ and IL-12 by activated T cells (83), it can also drive Th17-mediated responses, induce IL-17 production, and promote end-stage inflammation (Figure 3) (71). Therefore, IL-23 can exert effects similar to those of IL-17. Moreover, IL-23 might function in an autocrine manner to induce the production of TNF-α by macrophages and IL-12 by DCs (83). Immunization of Il23p19–/– mice with collagen results in fewer IL-17–producing T cells and limits the upregulation of IL-6 and TNF-α (84). Animal studies have so far revealed contradictory effects of IL-23 on tumor growth (85–87). Resistance to skin tumor formation in response
to chemical carcinogenesis was observed in Il23p19–/–
Moreover, the growth of transplanted tumors was restricted in hosts deficient in IL-23 or IL-23R (85). In this study, it was shown that, along with having an effect on tumor growth, IL-23 signal- ing results in upregulation of MMP9, increased angiogenesis, and decreased recruitment of CD8+ T cells to tumors. Therefore, IL-23–mediated inflammatory processes might provide a tumor- promoting microenvironment (85). However, in other studies, mice inoculated with IL-23–transduced tumor cells displayed increased tumor rejection, but this effect was only observed at very late time points after tumor inoculation (86, 87); CD8+ T cells had an important role in this IL-23–mediated antitumor activity (87).
IL-10 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-kB activation through ill-defined mech- anisms (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 lympho- cytes, 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 ApcMin/+ mice, which have a germline multiple intestinal neo- plasia (Min) mutation in one of their adenomatosis polyposis coli tumor suppressor genes and therefore develop intestinal adenomas (97). Transfer of wild-type Tregs into ApcMin/+ mice prevents the develop- ment 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-kB activation (Figure 3) (89, 90). Indeed, enhanced IL-12p40 produc- tion 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-kB recruitment to the Il12p40 pro- moter (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 activa- tion by IL-10 results in an antitumor effect, whereas STAT3 activa- tion by IL-6 is considered to be pro-tumorigenic. More recent stud- ies 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 down- regulation of MHC class I expression, leading to enhanced NK cell–mediated tumor cell lysis (105). Inhibition of the tumor stro- ma 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 inhibi- tory 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 acti- vate 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 pro- liferation 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 sug- gested 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 dra- matically opposing effects of IL-10 might depend on interactions with either cytokines or factors found in the tumor microenviron- ment, 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.
The Journal of Clinical Investigation