In the c-Myc/Tgfα transgenic model, MHC-1 is down-regulated and Rae1 is up-regulated on dysplastic hepatocytes targeting them for NK surveillance. However, malignant progression still succeeds, presumably due to insufficient NK numbers.49 NKT cells significantly increased in c-Myc/Tgfα dysplastic liver as it progressed toward

malignancy. Distinct NKT cell subsets can either promote (CD4+ NKT) or inhibit (iNKT) liver cancer50 (recently reviewed by Subleski et al.51) and can partially explain this observation. Bridging innate and adaptive immune systems, resident DCs are less functional in liver, Panobinostat but are still capable of priming antiviral T-cell responses sufficient for clearance. Upon viral escape, chronic liver inflammation renders liver DCs suppressed, as observed in chronically infected HCV patients showing a diminished ability to mature and prime T-cell proliferation and induce IFN-γ.52 Interaction between HCV core protein and DCs in culture results in reduced frequency

of pDC and direct inhibition of IFNα production.53 Core protein can also inhibit IL-12 production by DCs through an intracellular mechanism dependent on a combination of TLR4 signaling and cross-linking of the complement receptor,54 thereby contributing to a Th2 skewed microenvironment. HBV-infected patients have diminished pDC functions resulting in part from a specific HBV antigen (HBeAg).55 These findings suggest persistent viral infection and chronic inflammation deprive DC’s ability to prime T-cell surveillance, augmenting hepatocellular carcinogenesis. VX 809 Progesterone Circulating B cells from cirrhosis patients have been reported to be hyporesponsive to ex vivo CD40/TLR9 stimulation, as characterized by LTα secretion, IgG production, and T-cell allostimulation. A reduction in CD27+IgM+ memory B cells was also observed in cirrhosis patients.56 These changes support a reduced B-cell-mediated antiviral response, allowing persistent viral infection, associated inflammation, and HCC development. In contrast, results from an inflammatory skin model of HPV16 squamous cell carcinomas (SCC) suggest a more direct, tumor-promoting role for B cells, possibly by way of immunoglobulin

accumulation.57 Although controversial, increased levels of immunoglobulin in murine HCC models, serum from cirrhotic individuals, and HCC lesions58 all suggest a possible cause-and-effect linkage between the presence of immunoglobulin and HCC development. Previously, we established a murine de novo liver tumor model of adenoma and carcinoma by hydrodynamic injection of transposons containing myrAKT (AKT) and Δ90 β-catenin (β-CAT).59 We observed hepatocellular tumor development/progression to be largely dependent on B cells (authors’ unpubl. obs.). We also found that tumor infiltrating B cells express elevated levels of TNF-α (authors’ unpubl. obs.), suggesting that B cell-derived cytokines could be instrumental in tumor development/progression.