Regulatory Programs of B-cell Activation and Germinal Center Reaction Allow B-ALL Escape from CD19 CAR T-cell Therapy.
Journal
Cancer immunology research
ISSN: 2326-6074
Titre abrégé: Cancer Immunol Res
Pays: United States
ID NLM: 101614637
Informations de publication
Date de publication:
01 09 2022
01 09 2022
Historique:
received:
05
08
2021
revised:
13
04
2022
accepted:
23
06
2022
pubmed:
28
6
2022
medline:
9
9
2022
entrez:
27
6
2022
Statut:
ppublish
Résumé
Chimeric antigen receptor (CAR) T-cell therapy has led to tremendous successes in the treatment of B-cell malignancies. However, a large fraction of treated patients relapse, often with disease expressing reduced levels of the target antigen. Here, we report that exposing CD19+ B-cell acute lymphoblastic leukemia (B-ALL) cells to CD19 CAR T cells reduced CD19 expression within hours. Initially, CD19 CAR T cells caused clustering of CD19 at the T cell-leukemia cell interface followed by CD19 internalization and decreased CD19 surface expression on the B-ALL cells. CD19 expression was then repressed by transcriptional rewiring. Using single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing, we demonstrated that a subset of refractory CD19low cells sustained decreased CD19 expression through transcriptional programs of physiologic B-cell activation and germinal center reaction. Inhibiting B-cell activation programs with the Bruton's tyrosine kinase inhibitor ibrutinib increased the cytotoxicity of CD19 CAR T cells without affecting CAR T-cell viability. These results demonstrate transcriptional plasticity as an underlying mechanism of escape from CAR T cells and highlight the importance of combining CAR T-cell therapy with targeted therapies that aim to overcome this plasticity. See related Spotlight by Zhao and Melenhorst, p. 1040.
Identifiants
pubmed: 35759797
pii: 705260
doi: 10.1158/2326-6066.CIR-21-0626
pmc: PMC9444959
mid: NIHMS1820964
doi:
Substances chimiques
Antigens, CD19
0
Receptors, Antigen, T-Cell
0
Types de publication
Editorial
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1055-1068Subventions
Organisme : NCI NIH HHS
ID : K08 CA191026
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA191091
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2022 American Association for Cancer Research.
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