You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
Enhancing through epigenetics
A challenge for cancer immunotherapy is the need to turn cold, immune cell–excluded tumors into hot, inflamed tumors. Here, Yang et al. investigated the role of histone deacetylase 8 (HDAC8) in maintaining immune cell–excluded tumors. The authors showed that selective pharmacological inhibition of HDAC8 changed the epigenetic landscape of hepatocellular carcinoma cells, leading to production of T cell–recruiting chemokines. Treatment of hepatocellular carcinoma–bearing mice with the selective HDAC8 inhibitor resulted in increased infiltration of CD8+ T cells. Further, treatment with the HDAC8 inhibitor and immune checkpoint blockade led to enhanced control of tumors with no evidence of toxicity. Thus, epigenetic reprogramming used in combination with immunotherapy may be a promising approach for treating hepatocellular carcinomas and other immunologically cold tumors.
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.
- Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
This is an article distributed under the terms of the Science Journals Default License.
