Inflammation drives nitric oxide synthase 2 expression by γδ T cells and affects the balance between melanoma and vitiligo associated melanoma.

The high expression of inducible nitric oxide synthase (NOS2) by myeloid-derived suppressor cells (MDSCs) is a key mechanism of immune evasion in cancer. Recently we reported that NOS2 is also expressed by γδ T cells in melanoma, contributing to their polarization towards a pro-tumor phenotype. The molecular mechanisms underlying regulation of NOS2 expression in tumor-induced γδ T cells remain unexplored. By using the model of mice transgenic for the ret oncogene (Ret mice) that develops a spontaneous metastatic melanoma, we evidence that interleukin (IL)-1β and IL-6 drive NOS2 expression in γδ T cells. Indeed, their neutralization lessens the γδ T cell capacity to produce not only NOS2, but also IL-17 involved in the recruitment of MDSCs at the primary tumor site. The treatment also delayed tumor cell dissemination and induced vitiligo in a significant proportion of Ret mice. Interestingly, Ret mice developing a less aggressive melanoma, characterized by the spontaneous development of a concomitant autoimmune vitiligo, exhibit a weaker concentration of inflammatory cytokines and a reduction of tumor infiltrating γδ T cells expressing NOS2, when compared to Ret mice without any signs of vitiligo. Overall our results support that the level of inflammation at the tumor site regulates NOS2 expression by γδ T cells and the development of vitiligo associated melanoma.