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Class I HDAC inhibitors enhance antitumor efficacy and persistence of CAR-T cells by activation of the Wnt pathway.
- Source :
-
Cell reports [Cell Rep] 2024 Apr 23; Vol. 43 (4), pp. 114065. Date of Electronic Publication: 2024 Apr 04. - Publication Year :
- 2024
-
Abstract
- Epigenetic modification shapes differentiation trajectory and regulates the exhaustion state of chimeric antigen receptor T (CAR-T) cells. Limited efficacy induced by terminal exhaustion closely ties with intrinsic transcriptional regulation. However, the comprehensive regulatory mechanisms remain largely elusive. Here, we identify class I histone deacetylase inhibitors (HDACi) as boosters of CAR-T cell function by high-throughput screening of chromatin-modifying drugs, in which M344 and chidamide enhance memory maintenance and resistance to exhaustion of CAR-T cells that induce sustained antitumor efficacy both in vitro and in vivo. Mechanistically, HDACi decrease HDAC1 expression and enhance H3K27ac activity. Multi-omics analyses from RNA-seq, ATAC-seq, and H3K27ac CUT&Tag-seq show that HDACi upregulate expression of TCF4, LEF1, and CTNNB1, which subsequently activate the canonical Wnt/β-catenin pathway. Collectively, our findings elucidate the functional roles of class I HDACi in enhancing CAR-T cell function, which provides the basis and therapeutic targets for synergic combination of CAR-T cell therapy and HDACi treatment.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Benzamides pharmacology
Cell Line, Tumor
Immunotherapy, Adoptive methods
Receptors, Chimeric Antigen metabolism
T-Lymphocytes drug effects
T-Lymphocytes metabolism
T-Lymphocytes immunology
Histone Deacetylase 1 metabolism
Histone Deacetylase Inhibitors pharmacology
Wnt Signaling Pathway drug effects
Aminopyridines
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 43
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 38578828
- Full Text :
- https://doi.org/10.1016/j.celrep.2024.114065