Using hepatocellular carcinoma (HCC) models, Yang et al. showed that a histone deacetylase 8 (HDAC8)-selective inhibitor (PCI-34051) exhibits CD8+ T cell-dependent antitumor immunity. PCI-34051 reduced tumor growth in immunocompetent mice, with an increase in tumor-infiltrating CD8+ T cells and a decrease in Tregs. HDAC8 downregulation increased global and enhancer H3K27 acetylation and expression of T cell-trafficking chemokines. PCI-34051 plus anti-PD-L1 therapy eradicated HCC tumors, protected against rechallenge, and increased durable, circulating memory CD8+ T cells without evidence of toxicity.
Contributed by Shishir Pant
ABSTRACT: 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 protected against subsequent tumor rechallenge as a result of the induction of memory T cells and remained tumor-free for greater than 15 months. Collectively, our study demonstrates that selective HDAC8 inhibition elicits effective and durable responses to ICB by co-opting adaptive immunity through enhancer reprogramming.
Author Info: (1) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (2) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Ko
Author Info: (1) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (2) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (3) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (4) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (5) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (6) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (7) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (8) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (9) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (10) Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (11) AIDS Institute, The University of Hong Kong, Hong Kong SAR 999077, China. Department of Microbiology and Research Center for Infection and Immunity, The University of Hong Kong, Hong Kong SAR 999077, China. (12) Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. (13) Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen 518061, China. (14) Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (15) Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (16) Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (17) Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (18) Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore. Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore. SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 169857, Singapore. Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore. Singapore Gastric Cancer Consortium, Singapore 119228, Singapore. (19) AIDS Institute, The University of Hong Kong, Hong Kong SAR 999077, China. Department of Microbiology and Research Center for Infection and Immunity, The University of Hong Kong, Hong Kong SAR 999077, China. (20) Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. (21) Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (22) Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. (23) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. alfredcheng@cuhk.edu.hk.
