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

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.

Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10

“…Genetic risk of HCC was associated with MICA expression in chronic hepatitis C patients [ 4 , 5 ] as well as patients with HBV infection [ 6 ], thereby indicating hypofunction of anti-HCC immunity by MICA insufficiency as a therapeutic target [ 7 ]. In line with this hypothesis, restoration of membrane-bound MICA (mMICA) levels in HCC cells augmented natural killer (NK) cell-mediated anti-cancer activity in our and other groups’ studies [ 2 , 7 ], proving the concept of natural killer group 2D (NKG2D) signaling-mediated immunotherapy. We also demonstrated significant mMICA upregulation and reduction of levels of soluble MICA (sMICA), an immunological decoy, by an inhibitor of a disintegrin and metalloproteinase 10 (ADAM10) [ 2 ].…”

“…In line with this hypothesis, restoration of membrane-bound MICA (mMICA) levels in HCC cells augmented natural killer (NK) cell-mediated anti-cancer activity in our and other groups’ studies [ 2 , 7 ], proving the concept of natural killer group 2D (NKG2D) signaling-mediated immunotherapy. We also demonstrated significant mMICA upregulation and reduction of levels of soluble MICA (sMICA), an immunological decoy, by an inhibitor of a disintegrin and metalloproteinase 10 (ADAM10) [ 2 ]. ADAM10 is reported to be a MICA sheddase [ 8 ] and a promoter of HCC cell proliferation, invasion, and migration, which is correlated with worse prognosis and shorter survival in patients [ 9 ].…”

“…Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, with incidence and mortality continuing to increase [ 1 ]. Although interventional methods for controlling the leading risk factors, hepatitis B virus (HBV) and hepatitis C virus (HCV), have improved, pharmacologically therapeutic and preventive options for HCC still remain limited [ 2 ]. Therefore, further development of safe and cost-effective regimens for management of HCC is an urgent need.…”

Learning the Roles of the Hepatic Adaptive Immune System in Hepatocellular Carcinoma—Nature's Guide for Successful Cancer Immunotherapy

“…Still, the NK cell ligand MICA is downregulated in HCC, and was found in a genome-wide association study to be associated with HCC risk. 43,44 Similar findings were reported for the NK cell receptor KIR. 45 Clearly, better characterization of TILs, based on understanding the underlying immunobiology should help in generating better biomarkers for prognosis and hopefully different therapeutic modalities.…”

Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma

“…Vorinostat treatment of HCC cell lines can activate caspase-3 to promote cell apoptosis by TRAIL-DISC activation and autophagy leading to cell death [ 51 , 52 ]. In addition to its automatous effects, the antitumor activity of vorinostat can alter immune cell cytotoxicity to HCC [ 53 ]. The website shows a Phase I trial that is examining the side effects and dosage of vorinostat when given together with sorafenib tosylate, a kinase inhibitor drug approved for patients with advanced liver cancer.…”