Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai, 519000, China.
Gene Editing Technology Center of Guangdong Province, School of Medicine, Foshan University, Foshan, 528225, China.
EMBO Mol Med. 2024 Nov;16(11):3005-3025. doi: 10.1038/s44321-024-00136-9. Epub 2024 Sep 25.
Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8 T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8 T cells, where it functions as an intracellular checkpoint to negatively regulate CD8 T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8 T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.
视黄酸诱导基因 I（RIG-I）是一种参与固有免疫的模式识别受体，但它在适应性免疫中的作用，特别是在 CD8 T 细胞抗肿瘤免疫方面，仍不清楚。在这里，我们证明 RIG-I 在肿瘤浸润的 CD8 T 细胞中上调，在那里它作为细胞内检查点负调节 CD8 T 细胞功能并限制抗肿瘤免疫。从机制上讲，CD8 T 细胞中 RIG-I 的上调是由激活的 T 细胞诱导的，并直接抑制 AKT/糖酵解信号通路。此外，敲除 RIG-I 增强了过继转移 T 细胞对实体瘤的疗效，并且抑制 RIG-I 增强了对 PD-1 阻断的反应。总的来说，我们的研究将 RIG-I 鉴定为细胞内检查点和一种潜在的靶点，可用于减轻癌症免疫治疗中 T 细胞的抑制性限制，无论是单独使用还是与免疫检查点抑制剂联合使用。
