Interleukin 17 (IL-17) and its producing cells within the tumor microenvironment appear to promote tumor development and associate with survival of cancer patients. Here we investigated the role of the IL-17/IL- 17 receptor A (IL-17RA) axis in regulating melanoma progression and evaluated the therapeutic potential of blocking the IL-17/IL-17RA pathway. First, recombinant mouse IL-17 (gammamIL-17) treatment significantly increased cell proliferation of mouse B16F10 and human A375 and A2058. Silencing IL-17RA by small hairpin RNA (shRNA) in B16F10 cells reduced the gammamIL-17 elicited cell proliferation, migration and invasion, and significantly reduced VEGF and MMP production. Remarkably, knockdown of IL-17RA led to a significantly decreased capability of B16F10 cells to form tumors in vivo, similar to that in IL-17- deficient mice. Finally, local application of adenovirus delivering a shRNA against IL-17RA not only significantly suppressed tumor development, but also enhanced anti-tumor immunity by increasing the IFNgamma-expressing T cells and not Treg cells. Our results highlight the critical role of the IL-17/IL- 17RA pathway in tumor progression, and imply that targeting IL-17RA represents a promising therapeutic strategy.
