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dc.contributor.authorDavenport, AJ
dc.contributor.authorCross, RS
dc.contributor.authorWatson, KA
dc.contributor.authorLiao, Y
dc.contributor.authorShi, W
dc.contributor.authorPrince, HM
dc.contributor.authorBeavis, PA
dc.contributor.authorTrapani, JA
dc.contributor.authorKershaw, MH
dc.contributor.authorRitchie, DS
dc.contributor.authorDarcy, PK
dc.contributor.authorNeeson, PJ
dc.contributor.authorJenkins, MR
dc.date.accessioned2020-12-09T23:20:21Z
dc.date.available2020-12-09T23:20:21Z
dc.date.issued2018-02-27
dc.identifierpii: 1716266115
dc.identifier.citationDavenport, 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.
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/11343/253195
dc.description.abstractChimeric 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.
dc.languageEnglish
dc.publisherNATL ACAD SCIENCES
dc.titleChimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity
dc.typeJournal Article
dc.identifier.doi10.1073/pnas.1716266115
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.departmentMedicine and Radiology
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.source.titleProceedings of the National Academy of Sciences of USA
melbourne.source.volume115
melbourne.source.issue9
melbourne.source.pagesE2068-E2076
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1306210
melbourne.contributor.authorDarcy, Phillip
melbourne.contributor.authorPrince, Henry
melbourne.contributor.authorTrapani, Joseph
melbourne.contributor.authorKershaw, Michael
melbourne.contributor.authorNeeson, Paul
melbourne.contributor.authorShi, Wei
melbourne.contributor.authorCross, Ryan
melbourne.contributor.authorLiao, Yang
melbourne.contributor.authorBeavis, Paul
melbourne.contributor.authorRitchie, David
melbourne.contributor.authorJenkins, Misty-Rayna
dc.identifier.eissn1091-6490
melbourne.accessrightsOpen Access


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