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
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.