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CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

Bridgeman, John S., Ladell, Kristin Ingrid, Sheard, V. E., Miners, Kelly Louise, Hawkins, R. E., Price, David and Gilham, D. E. 2014. CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy. Clinical and Experimental Immunology 175 (2) , pp. 258-267. 10.1111/cei.12216

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Abstract

Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Wiley-Blackwell
ISSN: 0009-9104
Funders: BBSRC, Wellcome Trust, Cancer Research UK, European Commission FP6 programme ATTACK
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 29 September 2013
Last Modified: 16 Apr 2019 20:31
URI: http://orca.cf.ac.uk/id/eprint/61156

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