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

• DOI: 10.1016/j.celrep.2024.114065
• Publication Date: 2024-04-04T09:43:15Z
• Authors: Meng Zhu; Yingli Han; Tianning Gu; Rui Wang; Xiaohui Si; Delin Kong; Peng Zhao; Xiujian Wang; Jinxin Li; Xingyuan Zhai; Zebin Yu; Huan Lu; Jingyi Li; He Huang; Pengxu Qian
• Keywords: 0301 basic medicine; Receptors, Chimeric Antigen; QH301-705.5; T-Lymphocytes; Aminopyridines; Histone Deacetylase 1; Immunotherapy, Adoptive; Histone Deacetylase Inhibitors; Mice; 03 medical and health sciences; Cell Line, Tumor; Benzamides; Animals; Humans; Biology (General); CP: Cancer; Wnt Signaling Pathway

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.