Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity
AJ Davenport, RS Cross, KA Watson, Y Liao, W Shi, HM Prince, PA Beavis, JA Trapani, MH Kershaw, DS Ritchie, PK Darcy, PJ Neeson, MR Jenkins
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2018
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 indu..View full abstract
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We thank Sarah Ellis, Jill Danne, Chad Johnson, and Kylie Luong for assistance with microscopy; Ralph Rossi, Viki Milovac, and Sophie Curcio for assistance with flow cytometry; the animal facility technicians (Peter MacCallum Cancer Centre) for help with animal care; Melissa Henderson (Peter MacCallum Cancer Centre) for technical support; and Han Xian Aw Yeang for proofreading the manuscript. M.R.J. is supported by a National Health and Medical Research Council of Australia (NHMRC) career development fellowship and an NHMRC New Investigator Project Grant. A.J.D. is supported by a Fight Cancer Foundation PhD Scholarship. J.A.T. and P.J.N. are supported by an NHMRC Program Grant. P.K.D. is supported by an NHMRC Senior Research Fellowship. W.S. is supported by a Walter and Eliza Hall Institute Centenary Fellowship funded by Commonwealth Serum Laboratories.