Xu Xinyi, Chen Haotian, Ren Zhengxu, Xu Xiaomin, Wu Wei, Yang Haochen, Wang JinJiao, Zhang Yumeng, Zhou Qiuping, Li Hua, Zhang Shaoqing, Wang Haopeng, Xu Chenqi
Key Laboratory of Multi-cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Immunity. 2024 Dec 10;57(12):2755-2771.e8. doi: 10.1016/j.immuni.2024.11.005. Epub 2024 Nov 27.
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, E, into the conventional 28Z or BBZ CAR induced self-phase separation through cation-π interactions. E CAR formed a mature immunological synapse with the CD2 corolla to transduce efficient antigen and costimulatory signaling, although its tonic signaling remained low. Functionally, E 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, E 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.
嵌合抗原受体（CAR）-T细胞疗法的主要挑战包括抗原敏感性差和细胞持久性不足。在此，我们报告了一种通过利用CAR相分离来解决这些问题的方法。我们发现，将工程化的T细胞受体CD3ε基序E引入传统的28Z或BBZ CAR中，可通过阳离子-π相互作用诱导自相分离。E CAR与CD2花冠形成成熟的免疫突触，以转导有效的抗原和共刺激信号，尽管其持续性信号仍然较低。在功能上，E CAR-T细胞对低抗原肿瘤细胞表现出改善的信号传导和细胞毒性以及持久的肿瘤杀伤功能。在多个原发性和复发性小鼠肿瘤模型中，E CAR-T细胞在对抗血液和实体癌方面比传统CAR-T细胞发挥了更好的抗肿瘤功能。因此，本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细胞免疫的CAR工程策略。
