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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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The GPCR-Gαs-PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure

Victoria H Wu1,2, Bryan S Yung1, Farhoud Faraji3,4

  • 1Department of Pharmacology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.

Nature Immunology
|June 12, 2023
PubMed

Insights

G-protein-coupled receptors (GPCRs) on exhausted T cells hinder cancer immunotherapy. Targeting these Gαs-GPCRs may overcome resistance to immune checkpoint blockade (ICB) and improve durable responses.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) therapies targeting PD-1 and CTLA-4 have transformed cancer treatment.
  • However, a significant number of patients do not respond to ICB, necessitating novel therapeutic strategies.
  • G-protein-coupled receptors (GPCRs) are well-established drug targets but remain largely unexplored in immuno-oncology.

Purpose of the Study:

  • To investigate the role of GPCRs in T cell exhaustion and immunotherapy response.
  • To identify specific GPCRs that contribute to T cell dysfunction and resistance to ICB.
  • To explore potential druggable targets for enhancing ICB efficacy.

Main Methods:

  • Cross-integration of single-cell RNA-sequencing datasets from CD8+ T cells across 19 cancer types.
  • Identification of enriched Gαs-coupled GPCRs on exhausted CD8+ T cells.
  • Development of transgenic mice with chemogenetic CD8-restricted Gαs-DREADD for functional studies.

Main Results:

  • An enrichment of Gαs-coupled GPCRs, including EP2, EP4, A2AR, β1AR, and β2AR, was identified on exhausted CD8+ T cells.
  • These GPCRs were found to promote T cell dysfunction.
  • Activation of CD8-restricted Gαs signaling via a Gαs-PKA axis was shown to drive T cell dysfunction and immunotherapy failure.

Conclusions:

  • Gαs-coupled GPCRs represent a novel class of druggable immune checkpoints on exhausted CD8+ T cells.
  • Targeting these Gαs-GPCRs could potentially enhance patient responses to ICB immunotherapies.
  • This study opens new avenues for developing combination therapies to overcome ICB resistance in cancer.

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