An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and potentiates cancer immunotherapy
Xiangyu Chen, Jingxin Zhao, Shuai Yue, Ziyu Li, Xiang Duan, Yao Lin, Yang Yang, Junjian He, Leiqiong Gao, Zhiwei Pan, Xiaofan Yang, Xingxing Su, Min Huang, Xiao Li, Ye Zhao, Xuehui Zhang, Zhirong Li, Hu Li, Jianfang Tang, Yaxing Hao, Tian Qin, Yifei Wang, Lifan Xu, Qizhao Huang, Yingjiao Cao, Yaokai Chen, Bo Zhu, Yan Li, Fan Bai, Guozhong Zhang, Lilin Ye
Abstract
Abstract Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (T BYS ) cells are abundant and preserve functional memory properties in the TME. To leverage T BYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding T BYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing T BYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination.