Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy
Li, Wentao1,2,3; Qiu, Shizhen1; Chen, Jian4; Jiang, Shutan2; Chen, Wendong5; Jiang, Jingwei1,2; Wang, Fei1,2; Si, Wen6; Shu, Yilai4; Wei, Ping6
2020-08-18
发表期刊IMMUNITY
ISSN1074-7613
EISSN1097-4180
卷号53期号:2页码:456-+
发表状态已发表
DOI10.1016/j.immuni.2020.07.011
摘要

Clinical evidence suggests that poor persistence of chimeric antigen receptor-T cells (CAR-T) in patients limits therapeutic efficacy. Here, we designed a CAR with recyclable capability to promote in vivo persistence and to sustain antitumor activity. We showed that the engagement of tumor antigens induced rapid ubiquitination of CARs, causing CAR downmodulation followed by lysosomal degradation. Blocking CAR ubiquitination by mutating all lysines in the CAR cytoplasmic domain (CAR(KR)) markedly repressed CAR downmodulation by inhibiting lysosomal degradation while enhancing recycling of internalized CARs back to the cell surface. Upon encountering tumor antigens, CAR(KR)-T cells ameliorated the loss of surface CARs, which promoted their long-term killing capacity. Moreover, CAR(KR)-T cells containing 4-1BB signaling domains displayed elevated endosomal 4-1BB signaling that enhanced oxidative phosphorylation and promoted memory T cell differentiation, leading to superior persistence in vivo. Collectively, our study provides a straightforward strategy to optimize CAR-T antitumor efficacy by redirecting CAR trafficking.

收录类别SCI ; SCIE
语种英语
资助项目National Key R&D Program of China, China[2019YFA0111000] ; National Natural Science Foundation of China, China[31670919][31530022][31861133009][31621003] ; Science and Technology Commission of Shanghai Municipality of China, China[17411962000] ; Health and Family Planning Commission of Shanghai Municipality of China, China[2019SY059] ; [XDB29000000] ; [QYZDB-SSW-SMC048]
WOS研究方向Immunology
WOS类目Immunology
WOS记录号WOS:000561190600021
出版者CELL PRESS
WOS关键词T-CELL MEMORY ; SPARE RESPIRATORY CAPACITY ; OXIDATIVE STRESS ; C-CBL ; CAR ; COSTIMULATION ; LYMPHOCYTES ; EXPRESSION ; IMMUNOTHERAPY ; THERAPY
原始文献类型Article
引用统计
文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/123171
专题生命科学与技术学院_博士生
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
通讯作者Wu, Haitao; Xu, Chenqi; Wang, Haopeng
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol, Shanghai 200031, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Fudan Univ, Eye & ENT Hosp, ENT Inst & Dept Otorhinolaryngol, Shanghai 200031, Peoples R China
5.Southern Univ Sci & Technol, Dept Chem, Shenzhen 518055, Peoples R China
6.Peking Univ, Acad Adv Interdisciplinary Studies, Ctr Quantitat Biol & Peking Tsinghua Joint Ctr Li, Beijing 100871, Peoples R China
7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou 310024, Peoples R China
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
Li, Wentao,Qiu, Shizhen,Chen, Jian,et al. Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy[J]. IMMUNITY,2020,53(2):456-+.
APA Li, Wentao.,Qiu, Shizhen.,Chen, Jian.,Jiang, Shutan.,Chen, Wendong.,...&Wang, Haopeng.(2020).Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy.IMMUNITY,53(2),456-+.
MLA Li, Wentao,et al."Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy".IMMUNITY 53.2(2020):456-+.
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