中国科学院分子细胞科学卓越创新中心许琛琦等研究人员合作发现，嵌合抗原受体的相分离促进免疫突触成熟和持续的细胞毒性。相关论文于2024年11月27日在线发表在《免疫》杂志上。

研究人员表示，嵌合抗原受体（CAR）T细胞治疗的主要挑战包括抗原敏感性差和细胞持续性差。

研究人员通过利用CAR相分离提供了解决这些问题的方案。研究人员发现，将工程化的T细胞受体CD3ε结构域EB6I引入传统的28Z或BBZ CAR，能够通过阳离子-π相互作用诱导自我相分离。E_B6I CAR与CD2花环形成成熟的免疫突触，能够有效转导抗原和共刺激信号，尽管其基础信号传导保持较低。

功能上，E_B6I CAR-T细胞在低抗原肿瘤细胞上表现出改善的信号传导和细胞毒性，并维持持续的肿瘤杀伤功能。在多个原发性和复发性小鼠肿瘤模型中，E_B6I CAR-T细胞相比传统CAR-T细胞在血液和实体癌症中表现出更好的抗肿瘤功能。因此，该研究揭示了一种通过利用分子凝聚和信号整合来改善CAR-T细胞免疫功能的CAR工程策略。

附：英文原文

Title: Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity

Author: Xinyi Xu, Haotian Chen, Zhengxu Ren, Xiaomin Xu, Wei Wu, Haochen Yang, JinJiao Wang, Yumeng Zhang, Qiuping Zhou, Hua Li, Shaoqing Zhang, Haopeng Wang, Chenqi Xu

Issue&Volume: 2024-11-27

Abstract: Major challenges of chimeric antigen receptor (CAR)-T cell therapy include poor antigen sensitivity and cell persistence. Here, we report a solution to these issues by exploiting CAR phase separation. We found that incorporation of an engineered T cell receptor CD3ε motif, EB6I, into the conventional 28Z or BBZ CAR induced self-phase separation through cation-π interactions. EB6I CAR formed a mature immunological synapse with the CD2 corolla to transduce efficient antigen and costimulatory signaling, although its tonic signaling remained low. Functionally, EB6I CAR-T cells exhibited improved signaling and cytotoxicity against low-antigen tumor cells and persistent tumor-killing function. In multiple primary and relapsed murine tumor models, EB6I CAR-T cells exerted better antitumor functions than conventional CAR-T cells against blood and solid cancers. This study thus unveils a CAR engineering strategy to improve CAR-T cell immunity by leveraging molecular condensation and signaling integration.

DOI: 10.1016/j.immuni.2024.11.005

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00520-X