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The GPR171 pathway suppresses T cell activation and limits antitumor immunity

Author

Listed:
  • Yuki Fujiwara

    (University of Colorado Anschutz Medical Campus)

  • Robert J. Torphy

    (University of Colorado Anschutz Medical Campus)

  • Yi Sun

    (University of Colorado Anschutz Medical Campus)

  • Emily N. Miller

    (University of Colorado Anschutz Medical Campus)

  • Felix Ho

    (University of Colorado Anschutz Medical Campus)

  • Nicholas Borcherding

    (Washington University)

  • Tuoqi Wu

    (University of Colorado Anschutz Medical Campus)

  • Raul M. Torres

    (University of Colorado Anschutz Medical Campus)

  • Weizhou Zhang

    (University of Florida)

  • Richard D. Schulick

    (University of Colorado Anschutz Medical Campus)

  • Yuwen Zhu

    (University of Colorado Anschutz Medical Campus)

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.

Suggested Citation

  • 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, 2021. "The GPR171 pathway suppresses T cell activation and limits antitumor immunity," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26135-9
    DOI: 10.1038/s41467-021-26135-9
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    1. Hyunji Moon & Chanhyuk Min & Gayoung Kim & Deokhwan Kim & Kwanhyeong Kim & Sang-Ah Lee & Byeongjin Moon & Susumin Yang & Juyeon Lee & Seung-Joo Yang & Steve K. Cho & Gwangrog Lee & Chang Sup Lee & Chu, 2020. "Crbn modulates calcium influx by regulating Orai1 during efferocytosis," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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