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 ORCID: https://orcid.org/0000-0002-9856-2938, Sheard, V. E., Miners, Kelly Louise, Hawkins, R. E., Price, David ORCID: https://orcid.org/0000-0001-9416-2737 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:	12 Jun 2024 06:49
URI:	https://orca.cardiff.ac.uk/id/eprint/61156

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