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
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引用次数: 0
摘要
传统观点最初认为 PD-L1 是 PD-1 的惰性配体,但新出现的文献表明,PD-L1 在免疫细胞和癌细胞中具有细胞内在功能。与这些研究相一致,我们在此表明,通过细胞配体或激动抗体(包括临床上使用的抗体)与 PD-L1 结合,可有效抑制癌细胞中的 I 型干扰素通路。表达 PD-L1 的癌细胞中 I 型干扰素反应受阻,导致溶瘤病毒在体外和体内的疗效增强。一致的是,PD-L1 的表达标志着癌症患者的肿瘤外植体受到了溶瘤病毒的最佳感染。从机理上讲,PD-L1 促进了以糖酵解率提高为特征的新陈代谢转变,导致乳酸生成增加。反过来,乳酸盐又抑制了 I 型 IFN 反应。除了从机理上深入了解 PD-L1 的内在功能外,我们的研究结果还将有助于指导目前正在进行的将 PD-L1 抗体与溶瘤病毒疗法相结合的大量临床试验。
PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.
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.