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review series

Figure 3 Interactions between various cell types in the tumor microenvironment determine the effects of cytokines on tumor development and progression. Upon pathogen infection, both proinflammatory and antiinflammatory cytokines are produced by activated myeloid cells. In addition to their direct effects on tumor cell growth, survival, and invasive properties, cytokines can govern the functions of Th1 cells, NK cells, Tregs, and Th17 cells, all of which infiltrate the tumor. Treg-mediated suppression of antitumor CTL responses and induction of inflammatory Th17 cell–medi- ated responses contribute to tumor progression. Paradoxically, IL-10 can mediate the antitumor effects of Tregs. IL-23, TGF-β, IL-6, and TNF-α promote the development of Th17 cells, which have a central role in coordinating chronic inflammatory responses. IL-23 can induce the release of IFN-γ and IL-12 from activated T cells, TNF-α and IL-12 from APCs, and IL-17 from Th17 cells. In certain cases, cytokines such as TNF-α and IL-6 might be produced by tumor cells and function in an autocrine and paracrine fashion.

TRAIL is mainly produced by activated T cells and NK cells and is one of the major mediators of antitumor immunity. Unlike TNF-α, TRAIL is able to induce apoptosis in various tumor cell types but has only negligible effects on normal cells (Figure 2) (52). TRAIL-deficient mice or mice treated with TRAIL-specific neutralizing antibody exhibit increased susceptibility to experi- mentally induced and spontaneous tumors (53), suggesting an important role for endogenous TRAIL in tumor surveillance. When T cells are rendered TRAIL deficient, a much weaker graft- versus-tumor effect was observed (54). However, not all tumor cells are TRAIL sensitive, and NF-kB activation through TNF-α or other pro-survival factors confers on the tumor cells resis- tance to TRAIL-mediated cytotoxicity (39). Therefore, full real-

ization of the antitumor activity of TRAIL requires inhibition of NF-kB in the tumor cell or neutralization of NF-kB–activating, tumor-promoting cytokines, such as TNF-α.

IL-6 IL-6 is a potent pleiotropic inflammatory cytokine that is con- sidered a key growth-promoting and antiapoptotic factor (55). The IL-6 receptor complex is a heterodimer consisting of IL-6Rα and glycoprotein 130 (gp130), the latter of which is respon- sible for signal transduction (56). Activation of gp130 triggers phosphorylation of the STAT proteins STAT1 and STAT3 by JAK1 (Figure 2). STAT3 has a predominant role in IL-6 signal transduction, and its roles in malignant cell proliferation and


The Journal of Clinical Investigation


Volume 117

Number 5

May 2007

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