Jonathan J Hodgins, John Abou-Hamad, Colin Edward O'Dwyer, Ash Hagerman, Edward Yakubovich, Christiano Tanese de Souza, Marie Marotel, Ariel Buchler, Saleh Fadel, Maria M Park, Claire Fong-McMaster, Mathieu F Crupi, Olivia Joan Makinson, Reem Kurdieh, Reza Rezaei, Harkirat Singh Dhillon, Carolina S Ilkow, John C Bell, Mary-Ellen Harper, Benjamin H Rotstein, Rebecca C Auer, Barbara C Vanderhyden, Luc A Sabourin, Marie-Claude Bourgeois-Daigneault, David P Cook, Michele Ardolino
{"title":"PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.","authors":"Jonathan J Hodgins, John Abou-Hamad, Colin Edward O'Dwyer, Ash Hagerman, Edward Yakubovich, Christiano Tanese de Souza, Marie Marotel, Ariel Buchler, Saleh Fadel, Maria M Park, Claire Fong-McMaster, Mathieu F Crupi, Olivia Joan Makinson, Reem Kurdieh, Reza Rezaei, Harkirat Singh Dhillon, Carolina S Ilkow, John C Bell, Mary-Ellen Harper, Benjamin H Rotstein, Rebecca C Auer, Barbara C Vanderhyden, Luc A Sabourin, Marie-Claude Bourgeois-Daigneault, David P Cook, Michele Ardolino","doi":"10.1084/jem.20221721","DOIUrl":null,"url":null,"abstract":"<p><p>While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176258/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1084/jem.20221721","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/13 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
期刊介绍:
Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field.
Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions.
Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.