Superior efficacy and long-term survival benefit of HDAC8 and PD-L1 co-blockade in liver cancer immunotherapy
Refereed conference paper presented and published in conference proceedings

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AbstractThe heterogeneous responses to immune-checkpoint blockade therapy e.g. antiprogrammed death-ligand 1 (PD-L1) antibody are attributable to the complex interplay between a range of cancer-cell-autonomous cues and the immunosuppressive tumor microenvironment. Our integrative epigenomics and functional analysis has previously elucidated a critical role of histone deacetylase 8 (HDAC8) in hepatic carcinogenesis (Cancer Research 2015;75:4803-16). In this study, we aimed to investigate the therapeutic potential of a potent and highly-selective HDAC8-specific inhibitor PCI-34051 in preclinical hepatocellular carcinoma (HCC) model. Using an orthotopic HCC mouse model, we demonstrated that HDAC8 inhibition by PCI-34051 significantly reduced tumorigenicity in C57/BL6 (~5-fold; p<0.01) but not nude mice. Immune profiling revealed specific reduction in tumor-infiltrating regulatory T cells (Tregs; p<0.05), which was associated with significant increase in CD8+ T cells (p<0.05). The functional significance of Tregs was demonstrated by adoptive transfer, which completely abrogated PCI-34051-induced tumor growth inhibition. Notably, PCI-34051 treatment significantly enhanced the efficacy of anti-PD-L1 therapy (p<0.01). More importantly, combined PCI-34051 and anti-PD-L1 treatment resulted in complete tumor eradication in all of the co-treated mice, which exhibited significantly better survival rate than single treatment groups (p<0.05). Moreover, the combination therapy promoted long-term survival (>300 vs. 30 days in untreated control), which was associated with elevated CD8+ T effector and central memory cells. Our data suggest that selective chromatin modifications by HDAC8 alter the tumor immune surveillance program and demonstrate the potential of rational combinatorial epigenetic immunotherapy to fully unleash T-cell responses, leading to long-term remission of HCC.
All Author(s) ListAlfred Sze Lok CHENG, Weiqin YANG, Jingying ZHOU, Yu FENG, Hanyong SHUN, Stephen L. CHAN, Zhiwei CHEN, Ka-Fai TO, Joseph J. SUNG
Name of ConferenceCold Spring Harbor Asia on Cancer & Metabolism
Start Date of Conference26/03/2018
End Date of Conference30/03/2018
Place of ConferenceSuzhou
Country/Region of ConferenceChina
LanguagesEnglish-United Kingdom

Last updated on 2019-02-12 at 16:34