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Cancer Immunol Res. 2019 Sep;7(9):1472-1484. doi: 10.1158/2326-6066.CIR-18-0841. Epub 2019 Jul 2.

MERTK Acts as a Costimulatory Receptor on Human CD8+ T Cells.

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Department of Hematology, Center for Cancer Immune Therapy, University Hospital Herlev, Copenhagen, Denmark.
Department of Hematology, Center for Cancer Immune Therapy, University Hospital Herlev, Copenhagen, Denmark.
Translational Skin Cancer Research, University Hospital Essen, German Cancer Consortium (DKTK) Partner Site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Oncology, University Hospital Herlev, Copenhagen, Denmark.
Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Denmark.
Department of Immunology and Microbiology, Inflammation and Cancer Group, University of Copenhagen, Copenhagen, Denmark.


The TAM family of receptor tyrosine kinases (TYRO3, AXL, and MERTK) is known to be expressed on antigen-presenting cells and function as oncogenic drivers and as inhibitors of inflammatory responses. Both human and mouse CD8+ T cells are thought to be negative for TAM receptor expression. In this study, we show that T-cell receptor (TCR)-activated human primary CD8+ T cells expressed MERTK and the ligand PROS1 from day 2 postactivation. PROS1-mediated MERTK signaling served as a late costimulatory signal, increasing proliferation and secretion of effector and memory-associated cytokines. Knockdown and inhibition studies confirmed that this costimulatory effect was mediated through MERTK. Transcriptomic and metabolic analyses of PROS1-blocked CD8+ T cells demonstrated a role of the PROS1-MERTK axis in differentiation of memory CD8+ T cells. Finally, using tumor-infiltrating lymphocytes (TIL) from melanoma patients, we show that MERTK signaling on T cells improved TIL expansion and TIL-mediated autologous cancer cell killing. We conclude that MERTK serves as a late costimulatory signal for CD8+ T cells. Identification of this costimulatory function of MERTK on human CD8+ T cells suggests caution in the development of MERTK inhibitors for hematologic or solid cancer treatment.

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