Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study

Sci Rep. 2016 Dec 2:6:38407. doi: 10.1038/srep38407.

Abstract

Pharmacotherapeutic options are limited for hepatocellular carcinoma (HCC). Recently, we identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) gene as a susceptibility gene for hepatitis C virus-induced HCC in a genome-wide association study (GWAS). To prove the concept of HCC immunotherapy based on the results of a GWAS, in the present study, we searched for drugs that could restore MICA expression. A screen of the FDA-approved drug library identified the anti-cancer agent vorinostat as the strongest hit, suggesting histone deacetylase inhibitors (HDACis) as potent candidates. Indeed, the HDACi-induced expression of MICA specific to HCC cells enhanced natural killer (NK) cell-mediated cytotoxicity in co-culture, which was further reinforced by treatment with an inhibitor of MICA sheddase. Similarly augmented anti-tumor activity of NK cells via NK group 2D was observed in vivo. Metabolomics analysis revealed HDACi-mediated alterations in energy supply and stresses for MICA induction and HCC inhibition, providing a mechanism for the chemoimmunotherapeutic actions. These data are indicative of promising strategies for selective HCC innate immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / therapy*
  • Cell Line, Tumor
  • Coculture Techniques
  • Combined Modality Therapy
  • Cytotoxicity, Immunologic / drug effects
  • Gene Expression Regulation, Neoplastic*
  • Genome-Wide Association Study
  • Hep G2 Cells
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / immunology
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Immunotherapy / methods
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Liver Neoplasms / therapy*
  • Metabolome / drug effects
  • Metabolome / genetics
  • Metabolome / immunology
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • Peptide Hydrolases / pharmacology*
  • Small Molecule Libraries / pharmacology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / pathology
  • Vorinostat
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Histocompatibility Antigens Class I
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • MHC class I-related chain A
  • Neoplasm Proteins
  • Small Molecule Libraries
  • Vorinostat
  • Peptide Hydrolases