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

Research output: Contribution to journalArticlepeer-review

1 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 languageEnglish (US)
Article number5857
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

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

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