More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway

Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. 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 PD-L1 potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cells resulted in enhanced infection with oncolytic viruses in cancer cells in vitro and in vivo. PD-L1 expression marks tumor explants from cancer patients that are best infected by oncolytic viruses. Agonistic antibodies targeting PD-L1 further reduced type I IFN responses and enhanced oncolytic virus infection. Mechanistically, PD-L1 suppressed type I interferon by promoting Warburg metabolism, characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD‑L1‑expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials. PolyA RNA-seq of wild-type and PD-L1-KO TRAMP2-C2 cells with and without infection with the oncolytic virus VSVdelta51-YFP at an MOI of 0.1 for 8 hours