Type 17 immunity promotes the exhaustion of CD8+ T cells in cancer (original) (raw)
2021, Journal for ImmunoTherapy of 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, 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 hi Tim3 + 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-17producing cells as tumor-promoting cells facilitating CD8 + T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy. Recent advances revealed that at least two exhaustion states exist among PD-1 + CD8 + tumor-infiltrating lymphocytes (TILs) based
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