The GPR171 pathway suppresses T cell activation and limits antitumor immunity

Yuki Fujiwara; Robert J. Torphy; Yi Sun; Emily N. Miller; Felix Ho; Nicholas Borcherding; Tuoqi Wu; Raul M. Torres; Weizhou Zhang; Richard D. Schulick; Yuwen Zhu

doi:10.1038/s41467-021-26135-9

The GPR171 pathway suppresses T cell activation and limits antitumor immunity

Yuki Fujiwara, Robert J. Torphy, Yi Sun, Emily N. Miller, Felix Ho, Nicholas Borcherding, Tuoqi Wu, Raul M. Torres, Weizhou Zhang, Richard D. Schulick, Yuwen Zhu

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5 Scopus citations

Abstract

The recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.

Original language	English (US)
Article number	5857
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26135-9
State	Published - Dec 1 2021
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-021-26135-9

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title = "The GPR171 pathway suppresses T cell activation and limits antitumor immunity",

abstract = "The recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.",

author = "Yuki Fujiwara and Torphy, {Robert J.} and Yi Sun and Miller, {Emily N.} and Felix Ho and Nicholas Borcherding and Tuoqi Wu and Torres, {Raul M.} and Weizhou Zhang and Schulick, {Richard D.} and Yuwen Zhu",

note = "Funding Information: We thank the Mouse Genetics Core Facility at National Jewish Health for generating GPR171lacZ/lacZ mice, the flow cytometry core at the University of Colorado Cancer Center and the Support Grant (P30CA046934) for cell sorting, and the ImmunoMicro Flow Cytometry Shared Resource Laboratory at CU AMC (RRID: SCR_021321) for flow cytometry analyses. We also thank Dr. Haruhiko Furusawa at Department of Medicine at CU AMC for microscopic X-gal staining, Dr. Yi Zhang at Temple University for comments. This study is partially supported by the Wings of Hope for Pancreatic Research and the Research Scholar Grant, RSG-17-106-01 LIB, from the American Cancer Society. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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AU - Fujiwara, Yuki

AU - Torphy, Robert J.

AU - Sun, Yi

AU - Miller, Emily N.

AU - Ho, Felix

AU - Borcherding, Nicholas

AU - Wu, Tuoqi

AU - Torres, Raul M.

AU - Zhang, Weizhou

AU - Schulick, Richard D.

AU - Zhu, Yuwen

N1 - Funding Information: We thank the Mouse Genetics Core Facility at National Jewish Health for generating GPR171lacZ/lacZ mice, the flow cytometry core at the University of Colorado Cancer Center and the Support Grant (P30CA046934) for cell sorting, and the ImmunoMicro Flow Cytometry Shared Resource Laboratory at CU AMC (RRID: SCR_021321) for flow cytometry analyses. We also thank Dr. Haruhiko Furusawa at Department of Medicine at CU AMC for microscopic X-gal staining, Dr. Yi Zhang at Temple University for comments. This study is partially supported by the Wings of Hope for Pancreatic Research and the Research Scholar Grant, RSG-17-106-01 LIB, from the American Cancer Society. Publisher Copyright: © 2021, The Author(s).

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N2 - The recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.

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The GPR171 pathway suppresses T cell activation and limits antitumor immunity

Abstract

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