Single-cell data-driven design of armed oncolytic virus to boost cooperative innate-adaptive immunity against cancer
Jiliang Zhao, Han Wang, Chunlei Wang, Fan Li, Jingru Chen, Feilong Zhou, Yiping Zhu, Jinhua Chen, Jinming Liu, Hao Zheng, Nanxin Gong, Yazhuo Du, Yufan Zhang, Li Deng, Yuyao Du, Yanqin Liu, Yuanke Li, Na Li, Hongru Zhang, Dan Ding, Shouzhi Yu, Cuizhu Zhang, Ying‐Bin Yan, Wei Wang, Youjia Cao, Yuntao Zhang, Hongkai Zhang, Yuntao Zhang, Yuntao Zhang, Hongkai Zhang, Hongkai Zhang
Abstract
Oncolytic viruses have been considered promising cancer immunotherapies. However, oncovirotherapy agents impart durable responses in only a subset of cancer patients. Thus, exploring the cellular and molecular mechanisms underlying the heterogeneous responses in patients can provide guidance to develop more effective oncolytic virus therapies. Single-cell RNA sequencing (scRNA-seq) analysis of tumors responsive and non-responsive to oncovirotherapy revealed signatures of the tumor immune microenvironment associated with immune response. Thus, we designed and constructed an armed oncolytic virus, OV-5A, that expressed five genes with non-redundant functions. OV-5A treatment exhibits robust immune response against various tumors in multiple mouse models, peripheral blood mononuclear cell -patient-derived xenograft models, organoid-immune cell co-culture systems, and patient tissue sections by activating a cooperative innate-adaptive immune response against tumor cells. scRNA-seq analysis of complete responders and partial responders to OV-5A treatment guided the design of combination therapy of OV-5A. This data-driven approach paves an innovative way to rationalize the design of oncolytic virus and multi-agent combination therapies.