| First Author | Wu VH | Year | 2023 |
| Journal | Nat Immunol | PubMed ID | 37308665 |
| Mgi Jnum | J:337742 | Mgi Id | MGI:7495996 |
| Doi | 10.1038/s41590-023-01529-7 | Citation | Wu VH, et al. (2023) The GPCR-Galpha(s)-PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure. Nat Immunol |
| abstractText | 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 Galpha(s)-coupled GPCRs on exhausted CD8(+) T cells. These include EP(2), EP(4), 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 Galpha(s)-DREADD to activate CD8-restricted Galpha(s) signaling and show that a Galpha(s)-PKA signaling axis promotes CD8(+) T cell dysfunction and immunotherapy failure. These data indicate that Galpha(s)-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies. |
