CD3ζ‐based chimeric antigen receptors mediate T cell activation via cis‐ and trans‐signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy |
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| Authors: | J. S. Bridgeman K. Ladell V. E. Sheard K. Miners R. E. Hawkins D. A. Price D. E. Gilham |
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| Affiliation: | 1. Clinical and Experimental Immunotherapy Group, Department of Medical Oncology, Institute of Cancer Sciences, Manchester Academic Health Centre, The University of Manchester, , Manchester, UK;2. Institute of Infection and Immunity, Henry Wellcome Building, Cardiff University School of Medicine, , Cardiff, UK |
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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. |
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| Keywords: | gene therapy T cells therapy/immunotherapy |
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