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

Autor:	Xu X; 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., Chen H; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Ren Z; 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., Xu X; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China., Wu W; Cancer Center, The First Hospital of Jilin University, Changchun, China., Yang H; 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., Wang J; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Zhang Y; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Zhou Q; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China., Li H; 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., Zhang S; 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., Wang H; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: wanghp@shanghaitech.edu.cn., Xu C; 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; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. Electronic address: cqxu@sibcb.ac.cn.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2024 Dec 10; Vol. 57 (12), pp. 2755-2771.e8. Date of Electronic Publication: 2024 Nov 27.
DOI:	10.1016/j.immuni.2024.11.005
Abstrakt:	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 B6I , into the conventional 28Z or BBZ CAR induced self-phase separation through cation-π interactions. E B6I 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 B6I 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 B6I 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. Competing Interests: Declaration of interests Patents for CD19.E28Z and CD19.E(B6I)28Z CAR-T cell therapy have been applied. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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