PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway
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 J. F. Crupi, Olivia Makinson, Reem Kurdieh, Reza Rezaei, H.S. 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
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.