Inefficient CAR-proximal signaling blunts antigen sensitivity.
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
03
07
2019
accepted:
26
05
2020
pubmed:
8
7
2020
medline:
5
11
2020
entrez:
8
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32632291
doi: 10.1038/s41590-020-0719-0
pii: 10.1038/s41590-020-0719-0
doi:
Substances chimiques
Antigens, Neoplasm
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
848-856Subventions
Organisme : Austrian Science Fund FWF
ID : W 1224
Pays : Austria
Commentaires et corrections
Type : CommentIn
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