Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 175, Issue 2, Pages 258-267Publisher
WILEY
DOI: 10.1111/cei.12216
Keywords
gene therapy; T cells; therapy; immunotherapy
Categories
Funding
- BBSRC [BB/H001085/1]
- Wellcome Trust
- Cancer Research UK
- European Commission
- BBSRC [BB/H001085/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H001085/1] Funding Source: researchfish
- Wellcome Trust [100326/Z/12/Z] Funding Source: researchfish
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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 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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