Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response

• Published in: Signal transduction and targeted therapy Vol. 8; no. 1; p. 370
• Main Authors: Qiu, Miao-Zhen, Wang, Chaoye, Wu, Zhiying, Zhao, Qi, Zhao, Zhibin, Huang, Chun-Yu, Wu, Wenwei, Yang, Li-Qiong, Zhou, Zhi-Wei, Zheng, Yu, Pan, Hong-Ming, Liu, Zexian, Zeng, Zhao-Lei, Luo, Hui-Yan, Wang, Feng, Wang, Feng-Hua, Yang, Si-Yu, Huang, Meng-Xing, Lian, Zhexiong, Zhang, Haiyan, Xu, Rui-Hua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 21.09.2023; Nature Publishing Group UK
• Subjects: CD223 antigen; CD8 antigen; CXCL13 protein; Effector cells; Epstein-Barr virus; Gastric cancer; Immunity; Immunotherapy; Inflammation; Lymphocytes; Lymphocytes B; Lymphocytes T; Metastases; Phenotypes; Tumors
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-023-01622-1

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.