| Literature DB >> 32004441 |
Chuang Sun1, Peishun Shou2, Hongwei Du1, Koichi Hirabayashi1, Yuhui Chen1, Laura E Herring3, Sarah Ahn2, Yang Xu1, Kyogo Suzuki1, Guangming Li1, Ourania Tsahouridis1, Lishan Su2, Barbara Savoldo4, Gianpietro Dotti5.
Abstract
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.Entities:
Keywords: 4-1BB; CAR-CD3ζ; CAR-Ts; CD28; chimeric antigen receptor; cytokine release syndrome (CRS); druggable engineering; kinase; phosphatase; phosphorylation; synapse
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Year: 2020 PMID： 32004441 PMCID： PMC7397569 DOI： 10.1016/j.ccell.2019.12.014
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743