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

Here, the authors use computational screening and a chemogenetic analysis of transgenic mice to show that G alpha(s)-coupled G-protein-coupled receptors on exhausted CD8(+) T cells are involved in suppression of effector functions and inhibition of the protective effects of immune checkpoint immunotherapy. 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 G alpha(s)-coupled GPCRs on exhausted CD8(+) T cells. These include EP2, EP4, A(2A)R, beta(1)AR and beta(2)AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted G alpha(s)-DREADD to activate CD8-restricted G alpha(s) signaling and show that a G alpha(s)-PKA signaling axis promotes CD8(+) T cell dysfunction and immunotherapy failure. These data indicate that G alpha(s)-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.