학술논문
The GPCR–Gαs–PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure
Document Type
article
Author
Wu, Victoria H; Yung, Bryan S; Faraji, Farhoud; Saddawi-Konefka, Robert; Wang, Zhiyong; Wenzel, Alexander T; Song, Miranda J; Pagadala, Meghana S; Clubb, Lauren M; Chiou, Joshua; Sinha, Sanju; Matic, Marin; Raimondi, Francesco; Hoang, Thomas S; Berdeaux, Rebecca; Vignali, Dario AA; Iglesias-Bartolome, Ramiro; Carter, Hannah; Ruppin, Eytan; Mesirov, Jill P; Gutkind, J Silvio
Source
Nature Immunology. 24(8)
Subject
Language
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.