近日，美国北卡罗莱纳大学教堂山分校Gianpietro Dotti及其研究小组发现，THEMIS-SHP1的招募调整LCK介导的嵌合抗原受体重定向T细胞活化。相关论文发表在2020年2月10日出版的《癌细胞》杂志上。

Title: THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells

Author: Chuang Sun, Peishun Shou, Hongwei Du, Koichi Hirabayashi, Yuhui Chen, Laura E. Herring, Sarah Ahn, Yang Xu, Kyogo Suzuki, Guangming Li, Ourania Tsahouridis, Lishan Su, Barbara Savoldo, Gianpietro Dotti

Issue&Volume: January 30, 2020

Abstract: Chimeric antigen receptor (CAR) T cell costimulation mediated by CD28 and 4-1BB isessential for CAR-T cell-induced tumor regression. However, CD28 and 4-1BB differentiallymodulate kinetics, metabolism and persistence of CAR-T cells, and the mechanisms governingthese differences are not fully understood. We found that LCK recruited into the synapseof CD28-encoding CAR by co-receptors causes antigen-independent CAR-CD3ζ phosphorylationand increased antigen-dependent T cell activation. In contrast, the synapse formedby 4-1BB-encoding CAR recruits the THEMIS-SHP1 phosphatase complex that attenuatesCAR-CD3ζ phosphorylation. We further demonstrated that the CAR synapse can be engineeredto recruit either LCK to enhance the kinetics of tumor killing of 4-1BB CAR-T cellsor SHP1 to tune down cytokine release of CD28 CAR-T cells.

DOI: 10.1016/j.ccell.2019.12.014

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30584-7