The GPCR-Gα s -PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure.

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 Gα _s -coupled GPCRs on exhausted CD8 ⁺ T cells. These include EP ₂ , EP ₄ , A _2A R, β ₁ AR and β ₂ AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gα _s -DREADD to activate CD8-restricted Gα _s signaling and show that a Gα _s -PKA signaling axis promotes CD8 ⁺ T cell dysfunction and immunotherapy failure. These data indicate that Gα _s -GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)