Type 17 Immunity Promotes the Exhaustion of CD8+ T Cells in Cancer

Background Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8(+) tumor-infiltrating lymphocytes (TILs) remain unclear. Methods To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8(+) TILs in Il17a (-/-) mice, Il17a (Cre) R26 (DTA) mice, ROR gamma t inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4(+) T cells or CD11b(+)Gr-1(hi) myeloid cells in vivo, respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset. Results Depletion of CD4(+) T cells promotes the exhaustion of CD8(+) T cells with a concomitant increase in IL-17-producing CD8(+) T (Tc17) cells in the tumor. Unlike IFN-gamma-producing CD8(+) T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103(+)KLRG1(-)IL-7R alpha(hi) tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1(hi)Tim3(+)TOX(+) terminally exhausted CD8(+) T cells in the tumor. Blockade of IL-17 or ROR gamma t pathway inhibits exhaustion of CD8(+) T cells and also delays tumor growth in vivo. Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8(+) T cell exhaustion signature gene sets in multiple cancers. Conclusion IL-17-producing cells promote terminal exhaustion of CD8(+) T cells and tumor progression in vivo, which can be reversed by blockade of IL-17 or ROR gamma t pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8(+) T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.