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

Kim, Byung-Seok; Kuen, Da-Sol; Koh, Choong-Hyun; Kim, Hyung-Don; Chang, Seon Hee; Kim, Sehui; Jeon, Yoon Kyung; Park, Young-Jun; Choi, Garam; Kim, Jiyeon; Kang, Keon Wook; Kim, Hye Young; Kang, Suk-Jo; Hwang, Shin; Shin, Eui-Cheol; Kang, Chang-Yuil; Dong, Chen; Chung, Yeonseok

doi:10.1136/jitc-2021-002603

[해외논문] Type 17 immunity promotes the exhaustion of CD8 + T cells in cancer 원문보기

Journal for immunotherapy of cancer, v.9 no.6, 2021년, pp.e002603 -

Kim, Byung-Seok (Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul , South Korea) , Kuen, Da-Sol (Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul , South Korea) , Koh, Choong-Hyun (Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul , South Korea) , Kim, Hyung-Don (Graduate School of Medical Science and Engineering , Korea Advanced Institute of Science and Technology , Daejeon , South Korea) , Chang, Seon Hee (Department of Immunology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA) , Kim, Sehui (Department of Pathology, Seoul National University Hospital , Seoul National University College of Medicine , Seoul , South Korea) , Jeon, Yoon Kyung (Department of Pa) , Park, Young-Jun , Choi, Garam , Kim, Jiyeon , Kang, Keon Wook , Kim, Hye Young , Kang, Suk-Jo , Hwang, Shin , Shin, Eui-Cheol , Kang, Chang-Yuil , Dong, Chen , Chung, Yeonseok

Abstract ▼ AI-Helper

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.

Keyword

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