HDAC8 inhibition modulates liver tumor microenvironment: Rationale for combined epigenetic and immunotherapy

Abstract

The tumor microenvironment plays an instrumental role in cancer development and treatment response/resistance. Accumulating evidence is underscoring the fundamental importance of epigenetic regulation in tumor immune evasion. Epigenetic modification agents represent a ‘double-edged sword’, as they can exert divergent effects on cancer cells and the milieu of immune and stromal cells. Our integrative epigenomics analysis has elucidated previously unexplored functions of histone deacetylase 8 (HDAC8) in promoting β-catenin-dependent hepatocarcinogenesis through interacting with another critical chromatin regulator enhancer of zeste homology 2 (EZH2). Given the strong oncogenicity of HDAC8, we further investigated the therapeutic potential of a potent and highly-selective HDAC8-specific inhibitor PCI-34051. Using a hepatocellular carcinoma (HCC) orthotopic model in immunocompetent mice, we demonstrated that HDAC8 inhibition exerted a strong anti-tumorigenic effect (Ctrl vs. PCI: 6.32 vs. 0.33*10⁷ ROI intensity; p<0.01), which was comparable with programmed death-ligand 1 (PD-L1) blockade. Intriguingly, PCI-34051 significantly increased tumor-infiltrating multi-functional CD8⁺ T cells (~3-fold) and specifically reduced regulatory T cells (~2-fold). However, the level of PD-1⁺CD8⁺ T cells also increased, implicating potential T cell exhaustion. Our data suggest that selective chromatin modifications by HDAC8 and EZH2 alter the tumor immune surveillance program. By understanding the impact of epigenetic control on the liver tumor microenvironment, rational combinatorial epigenetic and immune checkpoint targeting has the potential to fully unleash T cell responses against HCC.