PD-L1 enhances the efficacy of the oncolytic virus VSVΔ51

Abstract

Oncolytic viruses (OVs) are a novel immunotherapy showing great promise in the treatment of cancer. Due to the impaired anti-viral response in cancer cells, OVs such as VSVΔ51 preferentially replicate in cancer cells relative to healthy cells. PD-L1 is a surface protein that binds to the inhibitory checkpoint receptor PD-1 to inhibit anti-cancer immunity in vivo. Previous work has suggested that PD-L1 has the ability to inhibit type I interferon signaling. Given that the type I interferon pathway is responsible for inducing the cellular anti-viral response, we hypothesized that PD-L1 will affect the replication of the OV VSVΔ51 in cancer cells. To this end, a PD-L1 knockout line was generated from the PD-L1-expressing mouse prostate cancer cell line TRAMP-C2 by CRISPR/Cas9 (TRAMP-C2 Cd274−/−). Indeed, WT TRAMP-C2 is more susceptible to VSVΔ51 infection and oncolysis compared to TRAMP-C2 Cd274−/− cells, and TRAMP-C2 Cd274−/− cells exhibit severe defects in viral replication and virion production. Similar results have been observed in a different cell type/line. Mechanistically, TRAMP-C2 Cd274−/− secrete greater amounts of IFN-β compared to WT TRAMP-C2 post-infection (with subsequent enhanced expression of IFN-stimulated anti-viral genes), and have altered signaling in response to IFN-β stimulation and VSVΔ51 infection. Similar results are observed following treatment with the viral mimic, poly(I:C). Importantly, all differences in infection between WT TRAMP-C2 and TRAMP-C2 Cd274−/− are abolished when the activity of IFNAR is blocked. Lastly, preliminary evidence suggests that CD80 surface expression is required for the function of PD-L1. Ultimately, we aim to characterize PD-1-independent functions of PD-L1.