[Research Articles] A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma

Insufficient T cell infiltration into noninflamed tumors, such as hepatocellular carcinoma (HCC), restricts the effectiveness of immune-checkpoint blockade (ICB) for a subset of patients. Epigenetic therapy provides further opportunities to rewire cancer-associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype remain incompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)–specific isozyme overexpressed in a variety of human cancers, thwarts HCC tumorigenicity in a T cell–dependent manner. The tumor-suppressive effect of selective HDAC8 inhibition was abrogated by CD8+ T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1251 silenced enhancer-target gene pairs that are enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer acetylation of H3K27 to reactivate production of T cell–trafficking chemokines by HCC cells, thus relieving T cell exclusion in both immunodeficient and humanized mouse models. In an HCC preclinical model, selective HDAC8 inhibition increased tumor-infiltrating CD8+ T cells and potentiated eradication of established hepatomas by anti–PD-L1 therapy without evidence of toxicity. Mice treated with HDAC8 and PD-L1 coblockade were...

Source: Science Translational Medicine - April 7, 2021 Category: Biomedical Science Authors: Yang, W., Feng, Y., Zhou, J., Cheung, O. K.-W., Cao, J., Wang, J., Tang, W., Tu, Y., Xu, L., Wu, F., Tan, Z., Sun, H., Tian, Y., Wong, J., Lai, P. B.-S., Chan, S. L., Chan, A. W.-H., Tan, P. B.-O., Chen, Z., Sung, J. J.-Y., Yip, K. Y.-L., To, K.-F., Cheng Tags: Research Articles Source Type: research