An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses
Guan Wang, Xi Kang, Katherine Chen, Tiffany Jehng, Lindsey Jones, Jie Chen, Xue F. Huang, Si–Yi Chen
Abstract
Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and immune cells leads to tumor resistance to oncolytic immunotherapy. In this study, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. We find that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.