The GPCR–Gαs–PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure

Victoria H. Wu, Bryan S. Yung, Farhoud Faraji, Robert Saddawi-Konefka, Zhiyong Wang, Alexander T. Wenzel, Miranda J. Song, Meghana S. Pagadala, Lauren M. Clubb, Joshua Chiou, Sanju Sinha, Marin Matic, Francesco Raimondi, Thomas S. Hoang, Rebecca Berdeaux, Dario A.A. Vignali, Ramiro Iglesias-Bartolome, Hannah Carter, Eytan Ruppin, Jill P. MesirovJ. Silvio Gutkind*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1318-1330
Number of pages13
JournalNature Immunology
Issue number8
StatePublished - Aug 2023
Externally publishedYes


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