Class I HDAC inhibitors enhance antitumor efficacy and persistence of CAR-T cells by activation of the Wnt pathway

• Published in: Cell reports (Cambridge) Vol. 43; no. 4; p. 114065
• Main Authors: Zhu, Meng, Han, Yingli, Gu, Tianning, Wang, Rui, Si, Xiaohui, Kong, Delin, Zhao, Peng, Wang, Xiujian, Li, Jinxin, Zhai, Xingyuan, Yu, Zebin, Lu, Huan, Li, Jingyi, Huang, He, Qian, Pengxu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.04.2024; Elsevier
• Subjects: Aminopyridines; Animals; Benzamides - pharmacology; CAR-T; Cell Line, Tumor; CP: Cancer; exhaustion; HDAC inhibitors; Histone Deacetylase 1 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Humans; Immunotherapy, Adoptive - methods; memory T cell subsets; Mice; Receptors, Chimeric Antigen - metabolism; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Wnt signaling pathway; Wnt Signaling Pathway - drug effects; exhaustion; HDAC inhibitors; Wnt signaling pathway; CAR-T; CP: Cancer; memory T cell subsets
• DOI: 10.1016/j.celrep.2024.114065
• ISSN: 2211-1247

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. [Display omitted] •Screening of chromatin-modifying drugs identifies class I HDACi as boosters of CAR-T cells•Class I HDACi enhance persistence and in vivo antitumor efficacy of CAR-T cells•Class I HDACi decrease HDAC1 expression and enhance H3K27ac activity•Multi-omics reveal class I HDACi activating the Wnt pathway in CAR-T cells In this study, Zhu et al. show that class I HDAC inhibitors, particularly M344 and chidamide, markedly improve persistence and antitumor efficacy of CAR-T cells by regulation of the HDAC1-H3K27ac axis and activation of the canonical Wnt/β-catenin signaling pathway.