MERTK Acts as a costimulatory receptor on human cd8 t cells

Marlies J.W. Peeters; Donata Dulkeviciute; Arianna Draghi; Cathrin Ritter; Anne Rahbech; Signe K. Skadborg; Tina Seremet; Ana Micaela Carnaz Simoes; Evelina Martinenaite; Holmfridur R. Halldorsdottir; Mads Hald Andersen; Gitte Holmen Olofsson; Inge Marie Svane; Lene Juel Rasmussen; Ozcan Met; Jeurgen C. Becker; Marco Donia; Claus Desler; Per Thor Straten

doi:10.1158/2326-6066.cir-18-0841

MERTK Acts as a costimulatory receptor on human cd8 t cells

Marlies J.W. Peeters^*, Donata Dulkeviciute, Arianna Draghi, Cathrin Ritter, Anne Rahbech, Signe K. Skadborg, Tina Seremet, Ana Micaela Carnaz Simoes, Evelina Martinenaite, Holmfridur R. Halldorsdottir, Mads Hald Andersen, Gitte Holmen Olofsson, Inge Marie Svane, Lene Juel Rasmussen, Ozcan Met, Jeurgen C. Becker, Marco Donia, Claus Desler, Per Thor Straten

^*Corresponding author for this work

13 Citations (Scopus)

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.

Original language	English
Journal	Cancer Immunology Research
Volume	7
Issue number	9
Pages (from-to)	1472-1484
Number of pages	13
ISSN	2326-6066
DOIs	https://doi.org/10.1158/2326-6066.cir-18-0841
Publication status	Published - 2019

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Peeters, M. J. W., Dulkeviciute, D., Draghi, A., Ritter, C., Rahbech, A., Skadborg, S. K., Seremet, T., Simoes, A. M. C., Martinenaite, E., Halldorsdottir, H. R., Andersen, M. H., Olofsson, G. H., Svane, I. M., Rasmussen, L. J., Met, O., Becker, J. C., Donia, M., Desler, C., & Straten, P. T. (2019). MERTK Acts as a costimulatory receptor on human cd8 t cells. Cancer Immunology Research, 7(9), 1472-1484. https://doi.org/10.1158/2326-6066.cir-18-0841

Peeters, MJW, Dulkeviciute, D, Draghi, A, Ritter, C, Rahbech, A, Skadborg, SK, Seremet, T, Simoes, AMC, Martinenaite, E, Halldorsdottir, HR, Andersen, MH, Olofsson, GH, Svane, IM , Rasmussen, LJ , Met, O, Becker, JC, Donia, M, Desler, C & Straten, PT 2019, 'MERTK Acts as a costimulatory receptor on human cd8 t cells', Cancer Immunology Research, vol. 7, no. 9, pp. 1472-1484. https://doi.org/10.1158/2326-6066.cir-18-0841

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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 Simoes, {Ana Micaela Carnaz} and Evelina Martinenaite and Halldorsdottir, {Holmfridur R.} and Andersen, {Mads Hald} and Olofsson, {Gitte Holmen} and Svane, {Inge Marie} and Rasmussen, {Lene Juel} and Ozcan Met and Becker, {Jeurgen C.} and Marco Donia and Claus Desler and Straten, {Per Thor}",

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doi = "10.1158/2326-6066.cir-18-0841",

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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 - Simoes, Ana Micaela Carnaz

AU - Martinenaite, Evelina

AU - Halldorsdottir, Holmfridur R.

AU - Andersen, Mads Hald

AU - Olofsson, Gitte Holmen

AU - Svane, Inge Marie

AU - Rasmussen, Lene Juel

AU - Met, Ozcan

AU - Becker, Jeurgen C.

AU - Donia, Marco

AU - Desler, Claus

AU - Straten, Per Thor

PY - 2019

Y1 - 2019

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.

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

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

M3 - Journal article

C2 - 31266785

AN - SCOPUS:85071784139

SN - 2326-6066

VL - 7

SP - 1472

EP - 1484

JO - Cancer Immunology Research

JF - Cancer Immunology Research

IS - 9

ER -

MERTK Acts as a costimulatory receptor on human cd8 t cells

Abstract

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