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ShanghaiTech University Knowledge Management System
| Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness | |
| 2023 | |
| 发表期刊 | CELL RESEARCH; (IF:28.1[JCR-2023],36.4[5-Year]) |
| ISSN | 1001-0602 |
| EISSN | 1748-7838 |
| 发表状态 | 已发表 |
| DOI | 10.1038/s41422-023-00789-0 |
| 摘要 | Tonic signaling of chimeric antigen receptor (CAR), i.e., the spontaneous CAR activation in the absence of tumor antigen stimulation, is considered to be a pivotal event controlling CAR-T efficacy. However, the molecular mechanism underlying the spontaneous CAR signals remains elusive. Here, we unveil that positively charged patches (PCPs) on the surface of the CAR antigen-binding domain mediate CAR clustering and result in CAR tonic signaling. For CARs with high tonic signaling (e.g., GD2.CAR and CSPG4.CAR), reducing PCPs on CARs or boosting ionic strength in the culture medium during ex vivo CAR-T cell expansion minimizes spontaneous CAR activation and alleviates CAR-T cell exhaustion. In contrast, introducing PCPs into the CAR with weak tonic signaling, such as CD19.CAR, results in improved in vivo persistence and superior antitumor function. These results demonstrate that CAR tonic signaling is induced and maintained by PCP-mediated CAR clustering. Notably, the mutations we generated to alter the PCPs maintain the antigen-binding affinity and specificity of the CAR. Therefore, our findings suggest that the rational tuning of PCPs to optimize tonic signaling and in vivo fitness of CAR-T cells is a promising design strategy for the next-generation CAR. |
| 学科门类 | Molecular Biology ; Cell Biology |
| URL | 查看原文 |
| 收录类别 | SCOPUS ; SCI |
| 语种 | 英语 |
| 资助项目 | Double First-Class Initiative Fund of ShanghaiTech University[2019YFA0111000] ; Youth Foundation of the National Natural Science Foundation of China[22010502700] ; Original Exploration Project of Shanghai Natural Science Foundation[82102863] ; National Natural Science Foundation of China[21ZR1480200] ; Shanghai Technology Innovation Project[82271149] ; CAS Young Scientists in Basic Research Program[21Y11912000] ; CAS Shanghai Branch Special Plan for Basic Research[YSBR-014] ; null[JCYJ-SHFY-2022-009] |
| WOS研究方向 | Cell Biology |
| WOS类目 | Cell Biology |
| WOS记录号 | WOS:000945327400002 |
| 出版者 | SPRINGERNATURE |
| 原始文献类型 | Article |
| Scopus 记录号 | 2-s2.0-85149398813 |
| 来源库 | SCOPUS |
| 引用统计 | 正在获取...
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| 文献类型 | 期刊论文 |
| 条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/286502 |
| 专题 | 生命科学与技术学院 生命科学与技术学院_PI研究组_范高峰组 生命科学与技术学院_PI研究组_王皞鹏组 生命科学与技术学院_硕士生 生命科学与技术学院_博士生 信息科学与技术学院_博士生 |
| 通讯作者 | Song, Xianmin; Xu, Chenqi; Wu, Haitao; Wang, Haopeng |
| 作者单位 | 1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 2.Fudan Univ, Eye & ENT Hosp, ENT Inst, Shanghai, Peoples R China 3.Fudan Univ, Eye & ENT Hosp, Dept Otorhinolaryngol, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci,State Key Lab Mol Biol, Shanghai, Peoples R China 5.Xiamen Shuangshi Middle Sch Fujian, Xiamen, Fujian, Peoples R China 6.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Hematol, Sch Med, Shanghai, Peoples R China 7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou, Zhejiang, Peoples R China 8.Shanghai Clin Res & Trial Ctr, Shanghai, Peoples R China 9.Austrian Acad Sci, CeMM, Res Ctr Mol Med, Vienna, Austria |
| 第一作者单位 | 生命科学与技术学院 |
| 通讯作者单位 | 生命科学与技术学院 |
| 第一作者的第一单位 | 生命科学与技术学院 |
| 推荐引用方式 GB/T 7714 | Chen, Jian,Qiu, Shizhen,Li, Wentao,et al. Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness[J]. CELL RESEARCH;,2023. |
| APA | Chen, Jian.,Qiu, Shizhen.,Li, Wentao.,Wang, Kun.,Zhang, Yu.,...&Wang, Haopeng.(2023).Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness.CELL RESEARCH;. |
| MLA | Chen, Jian,et al."Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness".CELL RESEARCH; (2023). |
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