Inefficient CAR-proximal signaling blunts antigen sensitivity.
Nat Immunol
; 21(8): 848-856, 2020 08.
Article
em En
| MEDLINE
| ID: mdl-32632291
Rational design of chimeric antigen receptors (CARs) with optimized anticancer performance mandates detailed knowledge of how CARs engage tumor antigens and how antigen engagement triggers activation. We analyzed CAR-mediated antigen recognition via quantitative, single-molecule, live-cell imaging and found the sensitivity of CAR T cells toward antigen approximately 1,000-times reduced as compared to T cell antigen-receptor-mediated recognition of nominal peptide-major histocompatibility complexes. While CARs outperformed T cell antigen receptors with regard to antigen binding within the immunological synapse, proximal signaling was significantly attenuated due to inefficient recruitment of the tyrosine-protein kinase ZAP-70 to ligated CARs and its reduced concomitant activation and subsequent release. Our study exposes signaling deficiencies of state-of-the-art CAR designs, which presently limit the efficacy of CAR T cell therapies to target tumors with diminished antigen expression.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Ativação Linfocitária
/
Linfócitos T CD8-Positivos
/
Receptores de Antígenos Quiméricos
/
Antígenos de Neoplasias
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Nat Immunol
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Áustria