IDDF2020-ABS-0215 Enhancer reprogramming by selective HDAC8 inhibition potentiates tumor remission and durable benefit by PD-L1 blockade. (18th November 2020)

• Record Type: Journal Article
• Authors: Yang, Weiqin; Feng, Yu; Zhou, Jingying; Wing Cheung, Otto Ka; Wu, Feng; Tan, Zhiwu; Xu, Liangliang; Sun, Hanyong; Tian, Yuan; Wong, John; Lai, Paul Bo San; Lam Chan, Stephen; Chan, Wing Hung; Tan, Patrick; Chen, Zhiwei; Yiu Sung, Joseph Jao; Lap Yip, Kevin Yuk; To, Ka Fai; Lok Cheng, Alfred Sze
• Is Part Of: Gut. Volume 69(2020)Supplement 2
• Page Start: A26
• Page End: A27
• Publication Date: 2020-11-18
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2020-IDDF.40
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: The insufficient T cell infiltration into non-inflamed tumors such as hepatocellular carcinoma (HCC) restricts the effectiveness of immune-checkpoint blockade (ICB) to a minority of patients. Epigenetic therapy provides new opportunities to rewire cancer transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype to sensitize ICB therapy remain incompletely defined. Here, we aimed to investigate the therapeutic efficacy and mechanistic basis of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)-specific isoform, in HCC development and ICB responsiveness. Methods: The immune-modulatory and anti-tumor effects of HDAC8 inhibition via a HDAC8-selective inhibitor, PCI34051, were determined in orthotopic HCC mouse models. Molecular mechanisms and functional significance of HDAC8 inhibition were conducted by genome-wide H3K27ac ChIP-seq and RNAseq in HCC patient specimens, cancer cell lines, NOD-SCID and humanized mouse models. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and PCI34051 was determined in orthotopic and spontaneous HCC mouse models. Results: Pharmacological inhibition of HDAC8 thwarted HCC tumorigenicity in immunocompetent but not immunodeficient mice. The tumor-suppressive effect of PCI34051 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 1, 251 silenced enhancer-target gene pairs that were enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer levels of H3K27 acetylation to reactivate T cell-trafficking chemokine production from HCC cells, thus relieving T cell exclusion in both NOD-SCID and humanized mouse models. In the HCC preclinical model, selective HDAC8 inhibition significantly increased tumor-infiltrating CD8 + T cells and potentiated eradication of established hepatoma by anti-PD-L1 therapy without a sign of toxicity. Importantly, mice treated with HDAC8/PD-L1 co-blockade were protected against subsequent tumor re-challenge with the induction of memory T cells and remained tumor-free for ≥15 months. Conclusions: Our study demonstrates that selective HDAC8 inhibition elicits effective and durable ICB responses by co-opting adaptive immunity via enhancer reprogramming, thereby providing a new strategy for effective combined epigenetic immunotherapy.