演題抄録

FACO Symposium

開催概要
開催回
第53回・2015年・京都
 

Identification of a HCV-induced HCC Associated Gene by GWAS and Its Therapeutic Application

演題番号 : FS2-2

[筆頭演者]
Kato Naoya:1 

1:Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo

 

Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). To identify the genetic susceptibility factors for HCV-induced HCC, a genome-wide association study (GWAS) was conducted. We found a novel locus (SNP) in the 5 prime flanking region of MICA to be strongly associated with HCV-induced HCC (Nat Genet 2011). We also found that risk allele of SNP was associated with lower MICA expression levels in HCV-induced HCC patients, indicating anti-hepatocarcinogenic effects of MICA upregulation. MICA is a well-known NKG2D ligand to be targeted by NK cells. Thus, we screened inducers of MICA expression using a reporter system, and found Vorinostat, a HDAC inhibitor, effectively induced MICA expression. In fact, the treatment of HCC cells with Vorinostat boosted NK cell cytotoxicity in coculture. Interestingly, this cytotoxic activity of NK cells against HCC cells was largely cancelled by anti-MICA Ab, indicating anti-hepatoma cell activity of Vorinostat via MICA expression. Moreover, the tumor growth was significantly suppressed by treatment with Vorinostat in immunodeficient NSG mice in which HCC cells were subcutaneously injected and NK cells from healthy donors were intravenously transferred. Interestingly, the antitumor effect of Vorinostat against tumors was largely abrogated by anti-NKG2D Ab, providing evidence that NKG2D-mediated regulation of NK cell activities serves as a critical pathway controlling antitumor effect of Vorinostat against HCC. Taking these results of proof of concept studies, it is anticipated to develop a novel immunotherapy for HCC.

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