Tumor-infiltrating IL-17-producing γδ T cells support the progression of tumor via promoting angiogenesis
Daiko Wakita, Kentaro Sumida, Yoichiro Iwakura, Hiroyoshi Nishikawa, Takayuki Ohkuri, Kenji Chamoto, Hidemitsu Kitamura, Takashi Nishimura
European Journal of immunology, A-accepted preprint doi: 10.1002/eji.200940157
Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing γδ T cells for tumor development in tumor-bearing mouse model. IL-17-/- mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL), γδ T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL- γδ T cells showed that circulating γδ T cells but not skin resident Vγ5+ γδT cells produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-β, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing γδ T cells. IL-17 production by tumor-infiltrating γδ T cells was blocked by anti-γδTCR or anti-NKG2D antibodies, indicating that these ligands expressed within the tumor microenvironment are involved in γδT-cell activation. The IL-17-producing TIL- γδ T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing γδ T cells generated in response to tumor microenvironment act as tumor-promoting cells by inducing angiogenesis.