Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, 510060, Guangzhou, China.
Signal Transduct Target Ther. 2023 Sep 21;8(1):370. 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-15CD8 T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15CD8 T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15CD8 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-15CD8 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.
EBV 相关胃癌（GC）表现出令人关注的免疫治疗反应。然而，EBV 印迹肿瘤免疫和治疗反应的细胞基础仍未确定。本研究旨在通过纵向单细胞 RNA 测序和配对单细胞 TCR/BCR 测序，精细描绘接受免疫化疗的人类 EBV(+)GC 的动态肿瘤免疫微环境。EBV(+)GC 表现出炎症免疫表型，T 细胞和 B 细胞浸润增加。免疫化疗触发效应 T 细胞的克隆复活和再激活，这些细胞决定治疗反应。通常，在 EBV(+)GC 患者中高度富集具有抗原特异性 ISG-15CD8 T 细胞群体，代表一种短暂的耗竭状态。重要的是，基线肿瘤内 ISG-15CD8 T 细胞可预测 GC 患者的免疫治疗反应性。在治疗后可以发现先前存在的 ISG-15CD8 T 细胞的重新出现的克隆型，这导致在反应性 EBV(+)肿瘤中产生 CXCL13 表达的效应细胞群体。然而，LAG-3 保留可能使 ISG-15CD8 T 细胞在非反应性 EBV(+)肿瘤中进入终末耗竭状态。相应地，抗 LAG-3 治疗可有效减少难治性 EBV(+)GC 患者的肿瘤负担。我们的研究结果描绘了 EBV 印迹治疗中 T 细胞免疫的独特作用，这可以为优化精准免疫治疗的合理设计提供依据。
