Journal
CANCER CELL
Volume 37, Issue 2, Pages 216-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.12.014
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Funding
- NCI Cancer Center Core Support Grant [P30-CA016086]
- National Cancer Institute, United States [R01-CA193140]
- National Institute of Allergy and Infectious Diseases, United States [R01-AI136990]
- Department of Defense, United States [W81XWH-18-1-0441]
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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.
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