B cells and antibody responses in virus-induced hepatocellular carcinoma

About This Grant

PROJECT SUMMARY In this exploratory project, our goal is to establish a physiological rodent model of chronic hepaciviral infection subsequently leading to the natural induction and progression of hepatocellular carcinoma (HCC), which can be immensely advantageous in understanding cancer immunobiology and translating future immunotherapies against virus-induced HCC. Our preliminary data using a rodent analog of hepatitis c virus, rat hepacivirus (RHV), highlighted a critical role for B cells for viral clearance during RHV infection. The lack of mature B cells in μMT mice prevented timely clearance of virus, resulting in persistent infection. Notably, persistent RHV infection of μMT mice led to an early elevation of alpha-fetoprotein (AFP) levels in serum, a commonly employed tumor marker for HCC, and subsequent development of HCC at 6-9 months post-infection. The nature of anti-tumoral T cell immunity in mice that develop persistent viremia due to the lack of B cells help is not clearly understood. Whether antigen-specific B cells can support T cell responses directly through antigen presentation or indirectly through local production of IgG or the recruitment of professional antigen presenting cells (e.g., dendritic cells) remains unclear. In this exploratory grant, we propose to use mice with intact B cells that show variable defects in these B cell attributes to elucidate whether the antigen-specific B cells, or B cell-specific antigen presentation or IgG production contribute to viral-induced HCC formation. We will use mice with intact B cells that show variable defects in B cell functions: a) B1-8i mice with a restricted B cell receptor repertoire, b) MHCIIf/fCD19cre conditional knockout mice that lack B-cell-specific antigen presentation, and c) AIDCre mice that lack activation-induced cytidine deaminase, where in B cells fail to undergo class-switch recombination or somatic hypermutation, with no IgG production. (Aim 1) Using these mice strains lacking several B cell attributes (e.g., antigen specificity, antigen presentation, and IgG production), we will elucidate how it influences tumor microenvironment, the progression of HCC tumors, and impacts anti-viral and anti-tumoral T cell responses. (Aim 2) To identify whether IgG antibodies are the effector functions of B cell-mediated clearance of viral persistence and HCC development, we will first unravel the viral target of IgG and passively transfer viral-specific IgG antibodies from RHV-infected WT mice into AIDCre mice during the longitudinal progression of tumor. If successful, our proposed mice strains developing human analogous virus-induced HCC progression will be exceptionally beneficial over artificial models of tumor induction in understanding B cell cancer immunobiology and informing future IgG based immunotherapies against viral-induced HCC.