爱泼斯坦－巴尔病毒（EBV）相关的胃癌（GC）表现出引人注目的免疫治疗反应。然而，EBV印记的肿瘤免疫和治疗反应的细胞基础仍未定义。本研究旨在通过纵向scRNA-seq和配对scTCR/BCR-seq对接受免疫化学治疗的EBV（+）GC的动态肿瘤免疫情况进行细致的表征。EBV（+）GC表现出一种炎症性免疫表型，具有增加的T细胞和B细胞浸润。免疫化学治疗促进了效应T细胞的克隆复苏和恢复活力，这些细胞在决定治疗反应。通常，特异性抗原的ISG-15+CD8+ T细胞人群在EBV（+）GC患者中富集，代表一种过渡性耗竭状态。重要的是，基线肿瘤内的ISG-15+CD8+ T细胞能够预测GC患者的免疫治疗响应性。治疗后可以发现预先存在的ISG-15+CD8+ T细胞的再出现的克隆类型，这导致了响应性EBV（+）肿瘤中CXCL13表达的效应细胞人群。然而，在不响应的EBV（+）肿瘤中，LAG-3的保留可能使ISG-15+CD8+ T细胞进入终末耗竭状态。相应地，抗LAG-3治疗可以有效减轻难治性EBV（+）GC患者的肿瘤负担。我们的结果揭示了EBV印记的治疗期间T细胞免疫在GC中的独特意义，这可以被利用来优化精准免疫治疗的合理设计。来源：2023年。中国西部医院，四川大学。

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.© 2023. West China Hospital, Sichuan University.