title: 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.
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.
authors.affiliation: Clinical and Experimental Immunotherapy Group, Department of Medical Oncology, Institute of Cancer Sciences, Manchester Academic Health Centre, The University of Manchester, Manchester, UK; Institute of Infection and Immunity, Henry Wellcome Building, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Bridgeman
authors.forename: K
authors.initials: K
authors.lastname: Ladell
authors.forename: V E
authors.initials: VE
authors.lastname: Sheard
authors.forename: K
authors.initials: K
authors.lastname: Miners
authors.forename: R E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: D A
authors.initials: DA
authors.lastname: Price
authors.forename: D E
authors.initials: DE
authors.lastname: Gilham
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology*; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D061625:Immunoreceptor Tyrosine-Based Activation Motif / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D015533:Transcriptional Activation / Q000235:genetics; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D000099192:CD69 Antigens; C121704:CD3 antigen, zeta chain
keywords: T cells; gene therapy; therapy/immunotherapy