期刊
CANCER IMMUNOLOGY RESEARCH
卷 7, 期 9, 页码 1472-1484出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-18-0841
关键词
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资金
- Danish Council for Independent Research [DFF-1331-00095B]
- Danish Cancer Society [R72-A4396-13-S2]
- Training Network for the Immunotherapy of Cancer - EU (IMMUTRAIN
- H2020 grant) [641549]
- Danielsen Foundation
- Axel Musfeldts fond
- Else og Mogens Wedell-Wedellsborg Fond
- AP Moller Fonden
- Den Bohmske Fond
- Dagmar Marshalls Fond
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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