Recombinant oncolytic adenovirus expressing a soluble PVR elicits long-term antitumor immune surveillance

Abstract

Oncolytic virotherapy (OVT) has been suggested to be effective. However, the suppressive effects of checkpoints and insufficient costimulatory signals limit OVT-induced antitumor immune responses. In this study, we constructed a replicative adenovirus, Ad5sPVR, that expresses the soluble extracellular domain of poliovirus receptor (sPVR). We showed that sPVR can bind to both T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and CD226, and the binding affinity of sPVR to TIGIT is stronger than that of PVR to CD226. In the H22 hepatocellular carcinoma (HCC) ascites model, Ad5sPVR treatment increased the infiltration of CD8+ T cells and the release of interferon (IFN)-γ, exhibiting an antitumor effect with long-term tumor-specific immune surveillance. In line with this, Ad5sPVR also effectively improved antitumor outcomes in solid tumors. In conclusion, while Ad5sPVR plays a role in oncolysis and transforms cold tumors into hot tumors, sPVR expressed by Ad5sPVR can block the PVR/TIGIT checkpoint and activate CD226, thereby greatly improving the efficacy of OVT. This study provides a new way to develop potential oncolytic viral drugs.