Recent clinical trials of inhibition of immune-checkpoints, programmed death-ligand 1 (PD-L1)/PD-1 axis, which elicits anti-tumour T-cell responses in various cancers, have also produced durable efficacy in a fraction of patients with advanced hepatocellular carcinoma (HCC). The heterogeneous responses to immune-checkpoint blockade therapy result from the complicated interplay between cancer-cell-autonomous cues and the immunosuppressive tumour microenvironment. Our previous epigenomics and functional analysis have elucidated an oncogenic 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 an HDAC8-specific inhibitor PCI-34051 in preclinical HCC model.Methods
To investigate the immune-modulatory and anti-tumour effects of PCI-34051, we established an orthotopic HCC mouse model via intrahepatic implantation of syngeneic Hepa1–6 hepatoma cells in immunocompetent C57BL/6 and immunodeficient nude mice. The mice have been treated with vehicle, PCI-34051, anti-PD-L1 antibody, or combined therapy for 2 weeks. The tumorigenicity was assessed by in vivo imaging and correlated with immune profiling.Results
We demonstrated that PCI-34051 significantly reduced HCC tumorigenicity in C57BL/6 (p<0.01) but not nude mice. Immune profiling revealed a specific reduction in tumor-infiltrating regulatory T cells (Tregs; p<0.05), 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 tumour 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 tumour eradication in all 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 days), which was associated with elevated CD8+T memory cells.Conclusions
Our data suggest that selective chromatin modifications by HDAC8 alter the tumour 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.