TY  - JOUR
AU  - Davenport, AJ
AU  - Cross, RS
AU  - Watson, KA
AU  - Liao, Y
AU  - Shi, W
AU  - Prince, HM
AU  - Beavis, PA
AU  - Trapani, JA
AU  - Kershaw, MH
AU  - Ritchie, DS
AU  - Darcy, PK
AU  - Neeson, PJ
AU  - Jenkins, MR
Y2  - 2020/12/09
Y1  - 2018/02/27
SN  - 0027-8424
UR  - http://hdl.handle.net/11343/253195
AB  - Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.
LA  - English
PB  - NATL ACAD SCIENCES
T1  - Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity
DO  - 10.1073/pnas.1716266115
IS  - Proceedings of the National Academy of Sciences of USA
VL  - 115
IS  - 9
SP  - E2068-E2076
L1  - /bitstream/handle/11343/253195/PMC5834689.pdf?sequence=1&isAllowed=y
ER  -