Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment

Kortylewski et al. Cancer Cell 15,114-123 (2009)

Speaker: 李建勳                                                  Time:14:00-15:00 04/22 2009

Commentator: 黎煥耀 老師                               Place: Room 601

Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in many cancers and important therein for cell proliferation, cell survival, angiogenesis, and even immune evasion. Activation of Stat3 occurs not only in tumor cells but also in many tumor-infiltrating immune cells such as macrophages, dendritic cells and T cells. This study reveals that Stat3 in these immune cells contributes to immunosuppression in tumor microenvironment. Two cytokines IL-12 (p35/p40) and IL-23 (p19/p40) play opposite roles in tumor formation; IL-12 inhibits tumor growth by inducing antitumor immunity while IL-23 promotes tumor progression. Here the authors show that, in murine tumor models, Stat3 up-regulates IL-23 production from tumor-associated macrophages, and suppresses IL-12 expression in tumor-infiltrating dendritic cells. Stat3 directly activates theIL-23/p19 promoter and inhibits c-Rel-mediated IL-12/p35 gene expression. Interestingly, regulatory T cells in the tumor microenvironment express IL-23R and respond to IL-23 to activate Stat3. Conditional knockout of Stat3 or antibody blockage of IL-23R reduces expression of IL-10 and Foxp3 in tumor-infiltrating regulatory T cells, indicating that Stat3 is also involved in immunosuppressive functions of the cells. This study emphasizes that, in tumor microenvironment, Stat3 activation in immune cells affects cytokine network and their interaction, shifting the immune balance toward immunosuppression that facilitates tumorigenesis.

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2.    Kortylewski, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat. Med. 11, 1314–1321. (2005)