The hylEfm Gene In Phylefm of Enterococcus Faecium Is Not Required In Pathogenesis of Murine Peritonitis

Authors

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 Mesirov
J Silvio Gutkind

Publication Date

8-1-2023

Journal

Nature Immunology

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.

Keywords

Mice, Animals, CD8-Positive T-Lymphocytes, Neoplasms, Signal Transduction, Mice, Transgenic, Immunotherapy, Tumor Microenvironment

DOI

10.1038/s41590-023-01529-7

PMID

37308665

PMCID

PMC10735169

PubMedCentral® Posted Date

December 2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes