| Autor: |
Paul B.S. Lai, Zhiwei Chen, Feng Wu, Hanyong Sun, Kevin Y. Yip, Jingying Zhou, Ka Fai To, Yuan Tian, Patrick Tan, Otto Ka-Wing Cheung, Alfred S. L. Cheng, Liangliang Xu, Stephen L. Chan, Wing Hung Chan, Weiqin Yang, Joseph J.Y. Sung, Yu Feng, Zhiwu Tan, John Wong |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Abstracts. |
| DOI: |
10.1136/gutjnl-2020-iddf.40 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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