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

Publication date: Available online 30 January 2020Source: Cancer CellAuthor(s): 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 DottiSummaryChimeric 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research