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The GPR171 pathway suppresses T cell activation and limits antitumor immunity

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...

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Bibliographic Details
Published in:Nature communications 2021-10, Vol.12 (1), p.5857-5857, Article 5857
Main Authors: Fujiwara, Yuki, Torphy, Robert J., Sun, Yi, Miller, Emily N., Ho, Felix, Borcherding, Nicholas, Wu, Tuoqi, Torres, Raul M., Zhang, Weizhou, Schulick, Richard D., Zhu, Yuwen
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Language:English
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Summary: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. Proliferative and effector functions of T cells are determined by T cell receptor signalling and modulated by activator and inhibitory co-receptors. Authors report here that the G-protein-coupled receptor GPR171 functions as a co-inhibitor of T cell signalling and might serve as a target for cancer immunotherapy.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-26135-9