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

Details

• Alternative Title:
  Nat Immunol
• Personal 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 A. A. ; Iglesias-Bartolome, Ramiro ; Carter, Hannah ; Ruppin, Eytan ; Mesirov, Jill P. ; Silvio Gutkind, J.
• Description:
  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|-coupled GPCRs on exhausted CD8| T cells. These include EP|, EP|, A|R, β|AR and β|AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gα|-DREADD to activate CD8-restricted Gα| signaling and show that a Gα|-PKA signaling axis promotes CD8| T cell dysfunction and immunotherapy failure. These data indicate that Gα|-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.
• Keywords:
  Animals CD8-Positive T-Lymphocytes Immunotherapy Mice Mice, Transgenic Neoplasms Signal Transduction Tumor Microenvironment
• Source:
  Nat Immunol. 24(8):1318-1330
• Pubmed ID:
  37308665
• Pubmed Central ID:
  PMC10735169
• Document Type:
  Journal Article
• Funding:
  1F31CA250488-01/CA/NCI NIH HHSUnited States/ ; F31 DE031961/DE/NIDCR NIH HHSUnited States/ ; R01-DK092590/DK/NIDDK NIH HHSUnited States/ ; R01CA247551/CA/NCI NIH HHSUnited States/ ; U24CA220341/CA/NCI NIH HHSUnited States/ ; R01DE026870/DE/NIDCR NIH HHSUnited States/ ; U24 CA248457/CA/NCI NIH HHSUnited States/ ; 1F31DE031961-01/DE/NIDCR NIH HHSUnited States/ ; F31CA257344/CA/NCI NIH HHSUnited States/ ; F32 DE029990/DE/NIDCR NIH HHSUnited States/ ; U24 CA220341/CA/NCI NIH HHSUnited States/ ; F32DE029990-01/DE/NIDCR NIH HHSUnited States/ ; F31 CA250488/CA/NCI NIH HHSUnited States/ ; ZIA BC011764/ImNIH/Intramural NIH HHSUnited States/ ; T15LM011271/LM/NLM NIH HHSUnited States/ ; U24CA248457/CA/NCI NIH HHSUnited States/ ; T15 LM011271/LM/NLM NIH HHSUnited States/ ; R01 AR072368/AR/NIAMS NIH HHSUnited States/ ; R01-AR-072368/AR/NIAMS NIH HHSUnited States/ ; T32 GM007752/GM/NIGMS NIH HHSUnited States/ ; U01 DE028227/DE/NIDCR NIH HHSUnited States/ ; R01 CA247551/CA/NCI NIH HHSUnited States/ ; R01 DE026870/DE/NIDCR NIH HHSUnited States/ ; U54 CA209891/CA/NCI NIH HHSUnited States/ ; U54CA209891/IP/NCIRD CDC HHSUnited States/ ; F31 CA257344/CA/NCI NIH HHSUnited States/ ; T32 DK007752/DK/NIDDK NIH HHSUnited States/ ; R01 DK092590/DK/NIDDK NIH HHSUnited States/
• Volume:
  24
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:c9cb3c581818fc63ad4a8f798768193e2ada09530e902d08f835ef05e9a38abe
• Download URL:
  https://stacks.cdc.gov/view/cdc/138310/cdc_138310_DS1.pdf
• File Type:
  [PDF - 3.88 MB ]