Abstract
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.
Highlights
The TAM receptor kinases—TYRO3, AXL, and MERTK—are negative regulators of inflammatory responses on antigenpresenting cells, like macrophages and dendritic cells (DC; ref. 1)
We show that PROS1–MERTK signaling in CD8þ T cells affected the function, gene expression, and metabolism of the cell
MERTK expression was confirmed by mRNA and protein expression on 3-day activated CD8þ T cells (Fig. 1G and H)
Summary
The TAM receptor kinases—TYRO3, AXL, and MERTK—are negative regulators of inflammatory responses on antigenpresenting cells, like macrophages and dendritic cells (DC; ref. 1). The TAM receptor kinases—TYRO3, AXL, and MERTK—are negative regulators of inflammatory responses on antigenpresenting cells, like macrophages and dendritic cells TAM receptor signaling is induced by the ligands growth arrest–specific gene 6 (GAS6) and protein S (PROS1), which act as bridging molecules by binding to phosphatidylserine The PtdSer–GAS6 or PtdSer–PROS1 complex subsequently activates the TAM receptors [3]. TAM receptors are reported to be expressed on DCs, macrophages, human. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/). Platelets, natural killer [NK(T)] cells, and B cells [4,5,6,7,8]. On cells of the innate immune system, TAM signaling dampens activation and promotes silent engulfment of apoptotic cells [9, 10]
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