IFNγ Promotes Papilloma Development by Up-regulating Th17-Associated Inflammation

IFN gamma plays a crucial role in immunity against a variety of transplanted tumors and methylcholanthrene-mediated tumorigenesis in mice. However, it is not clear whether and how endogenous IFN gamma influences 7,12-dimethylbenz(a)anthracene (DMBA)-induced and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papilloma development. We found here that IFN gamma expression was markedly up-regulated shortly after DMBA/TPA application to the skin. Surprisingly, neutralizing IFN gamma activity in vivo did not increase but rather decreased tumor development. Furthermore, IFN gamma receptor-deficient mice were also more resistant to papilloma development than their counterparts were. IFN gamma acted mainly in the promotion stage of papilloma development by enhancing TPA-induced leukocyte infiltration and epidermal hyperproliferation. The up-regulation of tumor necrosis factor alpha, interleukin (IL)-6, and transforming growth factor 13 was largely dependent on host IFN gamma responsiveness. Remarkably, up-regulation of both IL-17 expression in the skin and T helper 17 (Th17) cell number in draining lymph nodes after DMBA/TPA treatment was dependent on IFN gamma signaling. Depletion of IL-17 not only decreased the DMBA/TPA-induced inflammation and keratinocyte proliferation but also delayed papilloma development. These results show that IFN gamma, under certain conditions, may promote tumor development by enhancing a Th17-associated inflammatory reaction. [Cancer Res 2009;69(5):2010-7]