Treg-specific demethylated region activity in isolated regulatory t lymphocytes is a surrogate for disease severity in hepatocellular carcinoma

Abstract

In certain unique conditions like viral infections of the liver like hepatitis B (HBV) and hepatitis C (HCV), activation of Tregs may be associated with chronicity of the viral infections and subsequent predisposition to development of hepatocellular carcinoma (HCC) by the integrated viral genome. In parallel, potential persistence of Tregs activity may lead to immune evasion of cancerous cells and thus persistence of the carcinomatous conditions. In this study, we hypothesized that although the relative proportions of Tregs may remain unaltered in HCC, persistence of activity of Tregs may lead to immune evasion in advanced stages of HCC. To examine the issue of activation of Treg in liver cancer pathogenesis, we obtained liver biopsy and peripheral blood samples from patients with advanced grades of HCC, isolated Tregs, and examined the methylation status of "Treg-specific demethylated region" (TSDR), a key region whose methylation suppresses Treg activity and demethylation stimulates its genomic activity. This study provides evidence of demethylation of TSDR, increased gene expression examined by luciferase assays, and nuclear translocation of key transcription factors that function as gene enhancers in CD4+CD25+FoxP3 regulatory T cells in advanced grades of HCC.