CD3[zeta]-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

• Published in: Clinical and experimental immunology 2014-02, Vol.175 (2), p.258
• Main Authors: Bridgeman, J S, Ladell, K, Sheard, V E, Miners, K, Hawkins, R E, Price, D A, Gilham, D E
• Format: Article
• Language: English
• Subjects: Lymphocytes; Optimization; T cell receptors
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.12216

Summary 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) CD3[zeta] 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. [PUBLICATION ABSTRACT]