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

Abstract

BackgroundMultiple 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.MethodsTo 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, Il17aCreR26DTA 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-1hi myeloid cells in vivo, respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset.ResultsDepletion 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-7Rαhi 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-1hiTim3+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.ConclusionIL-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.

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

“…In addition, the fate of Th17 Cells is dictated by epigenetic modifications and also remodeled by the TME [ 160 ]. A recent study demonstrated that 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 suppression of the RORγt pathway [ 161 ]. This provides another target for epigenetic modulation in cancer immunotherapy.…”

Induction of Unique STAT Heterodimers by IL-21 Provokes IL-1RI Expression on CD8+T Cells, Resulting in Enhanced IL-1β Dependent Effector Function

“…A tumor-promoting function of IL-17-producing CD8 + T cells associates with poor patient survival in gastrointestinal cancers including gastric cancer and hepatocellular carcinoma ( 58 ), whereas the anti-tumor effect of IL-17-producing CD8+ T cells has been reported in a mouse B16 melanoma model ( 59 ). More recently, it has been demonstrated that Tc17 cells serve as one of the suppressive immune cells via promoting the exhaustion of CD8 + T cells in tumors under CD4-depleted conditions ( 60 ). The differentiation of Tc17 cells, analogous to IL-17-producing CD4 + (Th17) cells, is regulated by multiple cytokines including TGF-β, IL-6, IL-21, IL-23, and IL-1β and transcriptional factor RORγt.…”

No Time to Die, Born to Be Killers: Survival Is Accompanied by Exhaustion after an Endless Battle

“…Because ICB offered significant therapeutic improvement, a better characterization of the function and regulation of exhausted T cells is critical, as T Ex cells are major cell types responding to anti-PD-1/PD-L1 biologics ( Beltra et al, 2020 ). Among the different T Ex subsets, only PD-1 int CD44 hi progenitor T Ex responded efficiently to anti-PD-1/PD-L1 treatment compared to PD-1 hi CD44 int terminally exhausted T Ex ( Abdel-Hakeem et al, 2021 ; Beltra et al, 2020 ; Kim et al, 2021 ). After ICB, the circulatory subsets T Ex prog2 and T-bet high T Ex int expanded preferentially, and differentiation into different T Ex subsets is most likely affected by anti-PD-1/PD-L1 blockade ( Beltra et al, 2020 ).…”

“…T Ex cells alter effector functions, express inhibitory receptors (IR), and reduce immunoreactivity. Programmed cell death protein-1 (PD-1), lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin mucin-domain containing-3 (TIM-3), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are examples of IR’s ( Abdel-Hakeem et al, 2021 ; Khan et al, 2019 ; Kim et al, 2021 ; Yao et al, 2019 ). T Ex cells are distinguished by their heterogeneity, allowing classification into four different subsets ( Beltra et al, 2020 ).…”

“…While the progenitor and terminally exhausted T Ex subtypes have already been described ( Alfei et al, 2019 ; Khan et al, 2019 ; Kim et al, 2021 ; Yao et al, 2019 ), Beltra et al (2020) recently identified four distinct T Ex stages of exhaustion. As summarized in the figure, T Ex cells can be classified as progenitor, intermediate, or terminally exhausted T cells based on the expression of Ly108 (or signaling lymphocyte activation molecule family member 6 [SLAMF6]), CD69, and Ki67.…”