Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response
Miao‐Zhen Qiu, Chaoye Wang, Zhi‐Ying Wu, Qi Zhao, Zhibin Zhao, Chunyu Huang, Wen‐Wei Wu, Liqiong Yang, Zhiwei Zhou, Yu Zheng, Hongming Pan, Zexian Liu, Zhao-Lei Zeng, Hui Luo, Feng Wang, Feng‐Hua Wang, Siyu Yang, Meng‐Xing Huang, Zhe‐Xiong Lian, Haiyan Zhang, Rui‐Hua Xu
Abstract
Abstract Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15 + CD8 + T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15 + CD8 + T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15 + CD8 + T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15 + CD8 + T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy.