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Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity

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posted on 2023-05-11, 06:40 authored by AJ Davenport, RS Cross, KA Watson, Yang LiaoYang Liao, Wei ShiWei Shi, HM Prince, PA Beavis, JA Trapani, MH Kershaw, DS Ritchie, PK Darcy, PJ Neeson, Misty JenkinsMisty Jenkins
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 dualspecific 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.

Funding

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.

History

Publication Date

2018-02-12

Journal

Proceedings of the National Academy of Sciences

Volume

115

Issue

9

Pagination

9p. (p. E2068-E2076)

Publisher

National Academy of Sciences

ISSN

0027-8424

Rights Statement

© 2018 the Author(s). This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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