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

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@article{0830d4ef459248d7a7d13ba7bf3ef1b8,
title = "MERTK Acts as a Costimulatory Receptor on Human CD8+ T Cells",
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.",
author = "Peeters, {Marlies J W} and Donata Dulkeviciute and Arianna Draghi and Cathrin Ritter and Anne Rahbech and Skadborg, {Signe K} and Tina Seremet and {Carnaz Sim{\~o}es}, {Ana Micaela} and Evelina Martinenaite and Halld{\'o}rsd{\'o}ttir, {H{\'o}lmfridur R} and Andersen, {Mads Hald} and Olofsson, {Gitte Holmen} and Svane, {Inge Marie} and Rasmussen, {Lene Juel} and {\"O}zcan Met and Becker, {J{\"u}rgen C} and Marco Donia and Claus Desler and {Thor Straten}, Per",
note = "{\textcopyright}2019 American Association for Cancer Research.",
year = "2019",
month = sep,
doi = "10.1158/2326-6066.CIR-18-0841",
language = "English",
volume = "7",
pages = "1472--1484",
journal = "Cancer immunology research",
issn = "2326-6066",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

RIS

TY - JOUR

T1 - MERTK Acts as a Costimulatory Receptor on Human CD8+ T Cells

AU - Peeters, Marlies J W

AU - Dulkeviciute, Donata

AU - Draghi, Arianna

AU - Ritter, Cathrin

AU - Rahbech, Anne

AU - Skadborg, Signe K

AU - Seremet, Tina

AU - Carnaz Simões, Ana Micaela

AU - Martinenaite, Evelina

AU - Halldórsdóttir, Hólmfridur R

AU - Andersen, Mads Hald

AU - Olofsson, Gitte Holmen

AU - Svane, Inge Marie

AU - Rasmussen, Lene Juel

AU - Met, Özcan

AU - Becker, Jürgen C

AU - Donia, Marco

AU - Desler, Claus

AU - Thor Straten, Per

N1 - ©2019 American Association for Cancer Research.

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85071784139&partnerID=8YFLogxK

U2 - 10.1158/2326-6066.CIR-18-0841

DO - 10.1158/2326-6066.CIR-18-0841

M3 - Journal article

C2 - 31266785

VL - 7

SP - 1472

EP - 1484

JO - Cancer immunology research

JF - Cancer immunology research

SN - 2326-6066

IS - 9

ER -

ID: 57728694