THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells
THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells
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DOI：
10.1016/j.ccell.2019.12.014
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发表时间：
2020-02-10
期刊：
影响因子：
50.3
通讯作者：
Dotti, Gianpietro
中科院分区：
文献类型：
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作者：
Sun, Chuang;Shou, Peishun;Dotti, Gianpietro
CD28和4-1BB介导的嵌合抗原受体(CAR)T细胞共刺激在CAR-T细胞诱导的肿瘤消退中起重要作用。然而，CD28和4-1BB对CAR-T细胞的动力学、新陈代谢和持久性具有不同的调控作用，其调控机制尚不完全清楚。我们发现，LCK被共受体招募到编码CD28的CAR的突触中，导致抗原非依赖性CAR-CD3 Zeta磷酸化，并增加抗原依赖性T细胞的激活。相反，由4-1BB编码的CAR形成的突触招募THEMIS-SHP1磷酸酶复合体，从而减弱CAR-CD3 Zeta的磷酸化。我们进一步证明，CAR突触可以被设计成招募LCK来增强4-1BB CAR-T细胞的肿瘤杀伤动力学，或者SHP1来调节CD28 CAR-T细胞的细胞因子释放。
Chimeric antigen receptor (CAR) T cell costimulation mediated by CD28 and 4-1BB is essential for CAR-T cell-induced tumor regression. However, CD28 and 4-1BB differentially modulate kinetics, metabolism and persistence of CAR-T cells, and the mechanisms governing these differences are not fully understood. We found that LCK recruited into the synapse of CD28-encoding CAR by co-receptors causes antigen-independent CAR-CD3 zeta phosphorylation and increased antigen-dependent T cell activation. In contrast, the synapse formed by 4-1BB-encoding CAR recruits the THEMIS-SHP1 phosphatase complex that attenuates CAR-CD3 zeta phosphorylation. We further demonstrated that the CAR synapse can be engineered to recruit either LCK to enhance the kinetics of tumor killing of 4-1BB CAR-T cells or SHP1 to tune down cytokine release of CD28 CAR-T cells.