Wu and Yung et al. performed an integrated analysis of scRNAseq datasets from 19 cancer types and identified that a GPCR–Gαs signaling program correlated with tumor-infiltrating CD8+ T cell dysfunction and reduced response to ICB. Gαs ligands (PGE2, β1-AR) mediated activation of cAMP, and PKA simultaneously reduced T cell function and proliferation, increased inhibitory receptor expression, and polarized CD8+ T cells towards exhaustion. Gαs signaling activation exclusively on CD8+ T cells in CD8-GsD mice impaired T cell function, decreased antigen-specific CD8+ T cell infiltration, and abolished response to ICB against 4MOSC1 and MC38-OVA tumors.
Contributed by Shishir Pant
ABSTRACT: Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, β1AR and β2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs-DREADD to activate CD8-restricted Gαs signaling and show that a Gαs-PKA signaling axis promotes CD8+ T cell dysfunction and immunotherapy failure. These data indicate that Gαs-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.
Author Info: (1) Department of Pharmacology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Septerna, Inc., South San Francisco, CA, USA. (2) Department of P
Author Info: (1) Department of Pharmacology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Septerna, Inc., South San Francisco, CA, USA. (2) Department of Pharmacology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (3) Department of Otolaryngology-Head and Neck Surgery, University of California San Diego Health, La Jolla, CA, USA. UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (4) Department of Otolaryngology-Head and Neck Surgery, University of California San Diego Health, La Jolla, CA, USA. UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (5) UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (6) UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (7) UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (8) Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (9) Department of Pharmacology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (10) Biomedical Sciences Graduate Studies Program, University of California, San Diego, La Jolla, CA, USA. Internal Medicine Research Unit, Pfizer Worldwide Research, Cambridge, MA, USA. (11) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (12) Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy. (13) Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy. (14) Department of Pharmacology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (15) Department of Integrative Biology and Pharmacology, McGovern Medical School at UT Health Houston and CellChorus INC, Houston, TX, USA. (16) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (17) Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA. (18) UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (19) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (20) UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (21) Department of Pharmacology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. sgutkind@health.ucsd.edu.
