Mouse PVRIg has CD8+ T cell-specific coinhibitory functions and dampens antitumor immunity

Benjamin Murter, Xiaoyu Pan, Eran Ophir, Zoya Alteber, Meir Azulay, Rupashree Sen, Ofer Levy, Liat Dassa, Ilan Vaknin, Tal Fridman-Kfir, Ran Salomon, Achinoam Ravet, Ada Tam, Doron Levin, Yakir Vaknin, Evgeny Tatirovsky, Arthur Machlenkin, Andrew Mark Pardoll, Sudipto Ganguly

Research output: Contribution to journalArticle

Abstract

A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor-like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG. However, when compared with humans, less PVRIG transcript and surface protein was detected in murine CD8þ T cells ex vivo. However, activated CD8þ T cells upregulated PVRIG expression. In the mouse tumor microenvironment, infiltrating CD8þ T cells expressed PVRIG whereas its ligand, PVRL2, was detected predominantly on myeloid cells and tumor cells, mirroring the expression pattern in human tumors. PVRIG-deficient mouse CD8þ T cells mounted a stronger antigen-specific effector response compared with wild-type CD8þ T cells during acute Listeria monocytogenes infection. Furthermore, enhanced CD8þ T-cell effector function inhibited tumor growth in PVRIG-/- mice compared with wild-type mice and PD-L1 blockade conferred a synergistic antitumor response in PVRIG-/- mice. Therapeutic intervention with antagonistic anti-PVRIG in combination with anti-PD-L1 reduced tumor growth. Taken together, our results suggest PVRIG is an inducible checkpoint receptor and that targeting PVRIG-PVRL2 interactions results in increased CD8þ T-cell function and reduced tumor growth.

Original languageEnglish (US)
Pages (from-to)244-256
Number of pages13
JournalCancer immunology research
Volume7
Issue number2
DOIs
StatePublished - Feb 1 2019

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Immunity
T-Lymphocytes
Proteins
Tumor Microenvironment
poliovirus receptor
Neoplasms
Immunoglobulin Domains
Growth
Theilovirus
Ligands
Listeriosis
Natural Killer T-Cells
Listeria monocytogenes
Myeloid Cells
Natural Killer Cells
Membrane Proteins
Up-Regulation

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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Mouse PVRIg has CD8+ T cell-specific coinhibitory functions and dampens antitumor immunity. / Murter, Benjamin; Pan, Xiaoyu; Ophir, Eran; Alteber, Zoya; Azulay, Meir; Sen, Rupashree; Levy, Ofer; Dassa, Liat; Vaknin, Ilan; Fridman-Kfir, Tal; Salomon, Ran; Ravet, Achinoam; Tam, Ada; Levin, Doron; Vaknin, Yakir; Tatirovsky, Evgeny; Machlenkin, Arthur; Pardoll, Andrew Mark; Ganguly, Sudipto.

In: Cancer immunology research, Vol. 7, No. 2, 01.02.2019, p. 244-256.

Research output: Contribution to journalArticle

Murter, B, Pan, X, Ophir, E, Alteber, Z, Azulay, M, Sen, R, Levy, O, Dassa, L, Vaknin, I, Fridman-Kfir, T, Salomon, R, Ravet, A, Tam, A, Levin, D, Vaknin, Y, Tatirovsky, E, Machlenkin, A, Pardoll, AM & Ganguly, S 2019, 'Mouse PVRIg has CD8+ T cell-specific coinhibitory functions and dampens antitumor immunity', Cancer immunology research, vol. 7, no. 2, pp. 244-256. https://doi.org/10.1158/2326-6066.CIR-18-0460
Murter, Benjamin ; Pan, Xiaoyu ; Ophir, Eran ; Alteber, Zoya ; Azulay, Meir ; Sen, Rupashree ; Levy, Ofer ; Dassa, Liat ; Vaknin, Ilan ; Fridman-Kfir, Tal ; Salomon, Ran ; Ravet, Achinoam ; Tam, Ada ; Levin, Doron ; Vaknin, Yakir ; Tatirovsky, Evgeny ; Machlenkin, Arthur ; Pardoll, Andrew Mark ; Ganguly, Sudipto. / Mouse PVRIg has CD8+ T cell-specific coinhibitory functions and dampens antitumor immunity. In: Cancer immunology research. 2019 ; Vol. 7, No. 2. pp. 244-256.
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abstract = "A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor-like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG. However, when compared with humans, less PVRIG transcript and surface protein was detected in murine CD8{\th} T cells ex vivo. However, activated CD8{\th} T cells upregulated PVRIG expression. In the mouse tumor microenvironment, infiltrating CD8{\th} T cells expressed PVRIG whereas its ligand, PVRL2, was detected predominantly on myeloid cells and tumor cells, mirroring the expression pattern in human tumors. PVRIG-deficient mouse CD8{\th} T cells mounted a stronger antigen-specific effector response compared with wild-type CD8{\th} T cells during acute Listeria monocytogenes infection. Furthermore, enhanced CD8{\th} T-cell effector function inhibited tumor growth in PVRIG-/- mice compared with wild-type mice and PD-L1 blockade conferred a synergistic antitumor response in PVRIG-/- mice. Therapeutic intervention with antagonistic anti-PVRIG in combination with anti-PD-L1 reduced tumor growth. Taken together, our results suggest PVRIG is an inducible checkpoint receptor and that targeting PVRIG-PVRL2 interactions results in increased CD8{\th} T-cell function and reduced tumor growth.",
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T1 - Mouse PVRIg has CD8+ T cell-specific coinhibitory functions and dampens antitumor immunity

AU - Murter, Benjamin

AU - Pan, Xiaoyu

AU - Ophir, Eran

AU - Alteber, Zoya

AU - Azulay, Meir

AU - Sen, Rupashree

AU - Levy, Ofer

AU - Dassa, Liat

AU - Vaknin, Ilan

AU - Fridman-Kfir, Tal

AU - Salomon, Ran

AU - Ravet, Achinoam

AU - Tam, Ada

AU - Levin, Doron

AU - Vaknin, Yakir

AU - Tatirovsky, Evgeny

AU - Machlenkin, Arthur

AU - Pardoll, Andrew Mark

AU - Ganguly, Sudipto

PY - 2019/2/1

Y1 - 2019/2/1

N2 - A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor-like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG. However, when compared with humans, less PVRIG transcript and surface protein was detected in murine CD8þ T cells ex vivo. However, activated CD8þ T cells upregulated PVRIG expression. In the mouse tumor microenvironment, infiltrating CD8þ T cells expressed PVRIG whereas its ligand, PVRL2, was detected predominantly on myeloid cells and tumor cells, mirroring the expression pattern in human tumors. PVRIG-deficient mouse CD8þ T cells mounted a stronger antigen-specific effector response compared with wild-type CD8þ T cells during acute Listeria monocytogenes infection. Furthermore, enhanced CD8þ T-cell effector function inhibited tumor growth in PVRIG-/- mice compared with wild-type mice and PD-L1 blockade conferred a synergistic antitumor response in PVRIG-/- mice. Therapeutic intervention with antagonistic anti-PVRIG in combination with anti-PD-L1 reduced tumor growth. Taken together, our results suggest PVRIG is an inducible checkpoint receptor and that targeting PVRIG-PVRL2 interactions results in increased CD8þ T-cell function and reduced tumor growth.

AB - A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor-like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG. However, when compared with humans, less PVRIG transcript and surface protein was detected in murine CD8þ T cells ex vivo. However, activated CD8þ T cells upregulated PVRIG expression. In the mouse tumor microenvironment, infiltrating CD8þ T cells expressed PVRIG whereas its ligand, PVRL2, was detected predominantly on myeloid cells and tumor cells, mirroring the expression pattern in human tumors. PVRIG-deficient mouse CD8þ T cells mounted a stronger antigen-specific effector response compared with wild-type CD8þ T cells during acute Listeria monocytogenes infection. Furthermore, enhanced CD8þ T-cell effector function inhibited tumor growth in PVRIG-/- mice compared with wild-type mice and PD-L1 blockade conferred a synergistic antitumor response in PVRIG-/- mice. Therapeutic intervention with antagonistic anti-PVRIG in combination with anti-PD-L1 reduced tumor growth. Taken together, our results suggest PVRIG is an inducible checkpoint receptor and that targeting PVRIG-PVRL2 interactions results in increased CD8þ T-cell function and reduced tumor growth.

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