1).7, 8 In the current issue of Hepatology, the study by Fu et al.9 presents work describing a new Selleck INCB024360 subset of CD4+ T cells: CD4+ cytotoxic T cells (CTL) in HCC. The authors evaluated CD4+ CTLs in a large series of patients with HCC and chronic hepatitis B virus (HBV) infection, and found clinically important correlations between CD4+ CTL, survival, and recurrence rates in patients with HCC. CD4+ T cells are a diverse and growing group of distinct cell subsets with different function and cytokine secretion patterns. These different CD4+ T-cell subsets:

T helper 1 (TH1), TH2, TH17, and Tregs, carry out specialized immunoregulatory functions to either enhance or inhibit immune responses. In the study by Fu et al. we learn that in addition to the more established subsets of CD4+ T cells, CD4+ CTLs also play a role in HCC immunopathogenesis. CD4+ CTLs are a population of T cells that express granzyme and perforin that are effectors in mediating the cytotoxic activity on target cells.10 CD4+ CTLs kill target tumor cells by way of HLA Class II molecules and they are also found in the circulation only in disease states including autoimmune disease or viral infections.11 The study Romidepsin solubility dmso by Fu et al. provides the first report of decreased CD4+ CTLs frequency within the liver tumor tissue compared to nontumor liver regions in patients with HBV-related HCC.

The relative reductions of CD4+ CTLs within the tumor compared to nontumor areas demonstrate the immunosuppressive state of the tumor microenvironment within HCC. The finding of a CD4 T-cell subset with CTL features not only adds to the complexity of the immune infiltrate in HCC but also provides insight into the plasticity of CD4+ T cells in tumor immunity. HCC is a common, often lethal, complication that while most often emerges in the setting of cirrhosis it can occur even in the

absence of cirrhosis in chronic HBV. Most patients present with advanced tumors when treatment options are limited, despite the vigorous and early screening recommended in the American Association for the Study of Liver Diseases (AASLD) practice Thiamet G guidelines.12 Early detection of HCC development is a difficult clinical challenge. Current clinical practice for HCC screening includes alpha-fetoprotein (AFP) monitoring and liver ultrasound that have limited sensitivity, as AFP levels do not reliably correlate with disease, survival, or recurrence. This substandard sensitivity underlines the need for a biomarker that is able to detect early stage HCC, tumor progression, and/or recurrence after surgical treatment. Thus, it is not unexpected that biomarker discovery is a hot topic in HCC research. Several biomarkers are under investigation in HCC, including glycipan-3, des-gamma-carboxyprothrombin, and micro-RNAs; however, none of these are sufficiently sensitive and/or specific to warrant clinical utility. The data of Fu et al.