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-CD3ζ 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-CD3ζ 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.

中文翻译：

---

4-1BB的THEMIS-SHP1募集调整LCK介导的嵌合抗原受体重定向T细胞的启动。

CD28和4-1BB介导的嵌合抗原受体（CAR）T细胞共刺激对于CAR-T细胞诱导的肿瘤消退至关重要。但是，CD28和4-1BB差异性地调节CAR-T细胞的动力学，新陈代谢和持久性，而控制这些差异的机制尚不完全清楚。我们发现，LCK被共受体招募到CD28编码CAR的突触中会引起抗原非依赖性CAR-CD3ζ磷酸化并增加抗原依赖性T细胞活化。相反，编码4-1BB的CAR形成的突触募集了THEMIS-SHP1磷酸酶复合物，该复合物减弱了CAR-CD3ζ磷酸化。我们进一步证明，CAR突触可被工程化以募集LCK来增强4-1BB CAR-T细胞的杀伤动力学，或SHP1来调低CD28 CAR-T细胞的细胞因子释放。