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

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    Author
    Davenport, AJ; Cross, RS; Watson, KA; Liao, Y; Shi, W; Prince, HM; Beavis, PA; Trapani, JA; Kershaw, MH; Ritchie, DS; ...
    Date
    2018-02-27
    Source Title
    Proceedings of the National Academy of Sciences of USA
    Publisher
    NATL ACAD SCIENCES
    University of Melbourne Author/s
    Darcy, Phillip; Prince, Henry; Trapani, Joseph; Kershaw, Michael; Neeson, Paul; Shi, Wei; Cross, Ryan; Liao, Yang; Beavis, Paul; Ritchie, David; ...
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Medicine and Radiology
    Medical Biology (W.E.H.I.)
    Metadata
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    Document Type
    Journal Article
    Citations
    Davenport, A. J., Cross, R. S., Watson, K. A., Liao, Y., Shi, W., Prince, H. M., Beavis, P. A., Trapani, J. A., Kershaw, M. H., Ritchie, D. S., Darcy, P. K., Neeson, P. J. & Jenkins, M. R. (2018). Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115 (9), pp.E2068-E2076. https://doi.org/10.1073/pnas.1716266115.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253195
    DOI
    10.1073/pnas.1716266115
    Abstract
    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.

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