Complementarity-determining region clustering may cause CAR-T cell dysfunction.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 08 2023
10 08 2023
Historique:
received:
20
12
2021
accepted:
19
07
2023
medline:
14
8
2023
pubmed:
11
8
2023
entrez:
10
8
2023
Statut:
epublish
Résumé
Chimeric antigen receptor (CAR)-T cell therapy is rapidly advancing as cancer treatment, however, designing an optimal CAR remains challenging. A single-chain variable fragment (scFv) is generally used as CAR targeting moiety, wherein the complementarity-determining regions (CDRs) define its specificity. We report here that the CDR loops can cause CAR clustering, leading to antigen-independent tonic signalling and subsequent CAR-T cell dysfunction. We show via CARs incorporating scFvs with identical framework and varying CDR sequences that CARs may cluster on the T cell surface, which leads to antigen-independent CAR-T cell activation, characterized by increased cell size and interferon (IFN)-γ secretion. This results in CAR-T cell exhaustion, activation-induced cell death and reduced responsiveness to target-antigen-expressing tumour cells. CDR mutagenesis confirms that the CAR-clustering is mediated by CDR-loops. In summary, antigen-independent tonic signalling can be induced by CDR-mediated CAR clustering, which could not be predicted from the scFv sequences, but could be tested for by evaluating the activity of unstimulated CAR-T cells.
Identifiants
pubmed: 37563127
doi: 10.1038/s41467-023-40303-z
pii: 10.1038/s41467-023-40303-z
pmc: PMC10415375
doi:
Substances chimiques
Complementarity Determining Regions
0
Single-Chain Antibodies
0
Receptors, Antigen, T-Cell
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4732Informations de copyright
© 2023. Springer Nature Limited.
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