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

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

doi:10.1038/s41590-023-01529-7

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

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. MesirovJ. Silvio Gutkind^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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 Gα_s-coupled GPCRs on exhausted CD8⁺ T cells. These include EP₂, EP₄, A_2AR, β₁AR and β₂AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gα_s–DREADD to activate CD8-restricted Gα_s signaling and show that a Gα_s–PKA signaling axis promotes CD8⁺ T cell dysfunction and immunotherapy failure. These data indicate that Gα_s–GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.

Original language	English
Pages (from-to)	1318-1330
Number of pages	13
Journal	Nature Immunology
Volume	24
Issue number	8
DOIs	https://doi.org/10.1038/s41590-023-01529-7
State	Published - Aug 2023
Externally published	Yes

Funding

Funders	Funder number
University of Texas
National Institutes of Health	R01-DK092590
National Institutes of Health
National Cancer Institute	R01CA247551, F32DE029990-01, 1F31CA250488-01, U54CA209891, 5T32GM007752-40, NIH/NIDCR1F31DE031961-01, U24CA220341, U24CA248457, F31CA257344
National Cancer Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01-AR-072368
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Dental and Craniofacial Research	R01DE026870, U01DE028227
National Institute of Dental and Craniofacial Research
U.S. National Library of Medicine	T15LM011271
U.S. National Library of Medicine
University of California, San Diego
University of Pittsburgh
Israel National Road Safety Authority

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41590-023-01529-7

Cite this

Wu, V. H., Yung, B. S., Faraji, F., Saddawi-Konefka, R., Wang, Z., Wenzel, A. T., Song, M. J., Pagadala, M. S., Clubb, L. M., Chiou, J., Sinha, S., Matic, M., Raimondi, F., Hoang, T. S., Berdeaux, R., Vignali, D. A. A., Iglesias-Bartolome, R., Carter, H., Ruppin, E., ... Gutkind, J. S. (2023). The GPCR–Gα_s–PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure. Nature Immunology, 24(8), 1318-1330. https://doi.org/10.1038/s41590-023-01529-7

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title = "The GPCR–Gαs–PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure",

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.",

author = "Wu, {Victoria H.} and Yung, {Bryan S.} and Farhoud Faraji and Robert Saddawi-Konefka and Zhiyong Wang and Wenzel, {Alexander T.} and Song, {Miranda J.} and Pagadala, {Meghana S.} and Clubb, {Lauren M.} and Joshua Chiou and Sanju Sinha and Marin Matic and Francesco Raimondi and Hoang, {Thomas S.} and Rebecca Berdeaux and Vignali, {Dario A.A.} and Ramiro Iglesias-Bartolome and Hannah Carter and Eytan Ruppin and Mesirov, {Jill P.} and Gutkind, {J. Silvio}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = aug,

doi = "10.1038/s41590-023-01529-7",

language = "אנגלית",

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Wu, VH, Yung, BS, Faraji, F, Saddawi-Konefka, R, Wang, Z, Wenzel, AT, Song, MJ, Pagadala, MS, Clubb, LM, Chiou, J, Sinha, S, Matic, M, Raimondi, F, Hoang, TS, Berdeaux, R, Vignali, DAA, Iglesias-Bartolome, R, Carter, H, Ruppin, E, Mesirov, JP & Gutkind, JS 2023, 'The GPCR–Gα_s–PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure', Nature Immunology, vol. 24, no. 8, pp. 1318-1330. https://doi.org/10.1038/s41590-023-01529-7

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T1 - The GPCR–Gαs–PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure

AU - Wu, Victoria H.

AU - Yung, Bryan S.

AU - Faraji, Farhoud

AU - Saddawi-Konefka, Robert

AU - Wang, Zhiyong

AU - Wenzel, Alexander T.

AU - Song, Miranda J.

AU - Pagadala, Meghana S.

AU - Clubb, Lauren M.

AU - Chiou, Joshua

AU - Sinha, Sanju

AU - Matic, Marin

AU - Raimondi, Francesco

AU - Hoang, Thomas S.

AU - Berdeaux, Rebecca

AU - Vignali, Dario A.A.

AU - Iglesias-Bartolome, Ramiro

AU - Carter, Hannah

AU - Ruppin, Eytan

AU - Mesirov, Jill P.

AU - Gutkind, J. Silvio

PY - 2023/8

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N2 - 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.

AB - 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.

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