IL-17-producing CD8+ T cells induce myeloid-derived suppressor cell chemotaxis and correlate with human cancer progression

Tumor progression is a multistage process involving cross-talk between tumor-infiltrating immune cells and tumor cells within the tumor microenvironment. IL-17-producing CD8+ T cells (Tc17 cells) represent a newly discovered T-cell subset, but their nature, regulation, function, and clinical relevance in human tumors are presently unknown. We found that Tc17 cells accumulated in tumors of 103 gastric cancer patients, and that increased Tc17 cell percentage independently predicted reduced overall survival. Tumor-activated macrophages secreted IL-6, IL-1β, and IL-23, which together favored Tc17 cell polarization, and this process was negatively regulated by tumor-infiltrating regulatory T cells (Tregs) through a cell contact-dependent mechanism. Supernatants from Tc17 cell cultures induced CXCL12 chemokine production by tumor cells, which in turn promoted CXCR4-dependent migration of myeloid-derived suppressor cells (MDSCs) and subsequent impairment of anti-tumor CD8+ cytotoxic T cell (CTL) function via a cell contact-dependent mechanism. Collectively, this study identifies a novel regulatory network involving Tc17 cells, which in conjunction with Macrophage, tumor cells, and MDSCs exert an immunosuppressive effect within the tumor microenvironment. Efforts to inhibit Tc17 cell activity might therefore prove a valuable strategy in anti-cancer therapy.