Type 17 immunity promotes the exhaustion of CD8+ T cells in cancer

Abstract

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^CreR26^DTA mice, RORγt 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-γ-producing CD8⁺ T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103⁺KLRG1^-IL-7Rα^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^hiTim3⁺TOX⁺ terminally exhausted CD8⁺ T cells in the tumor. Blockade of IL-17 or RORγt 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 RORγt 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.

Keywords: CD8-positive T-lymphocytes; cytokines; cytotoxicity; immunologic; lymphocytes; tumor microenvironment; tumor-infiltrating.