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"Antitumor Activity of Type III Interferon in BNL Hepatoma Mouse Model"

Walid Abushahba
Department of Biochemistry & Molecular Biology

B.S. 2000, Rutgers University

Thesis Advisor: Sergei Kotenko, Ph.D.

Associate Professor

Department of Biochemistry and Molecular Biology

Friday, December 18, 2009
1:00 p.m., MSB E-609b


Recently discovered type III IFN (IFN-) has been demonstrated to exhibit significant antitumor activity in a B16 melanoma mouse model. In contrast to IFN-, IFN- acts in a tissue specific manner and may offer a safer and more specific therapeutic alternative. In the present thesis, we developed a murine transplantable hepatoma model to evaluate the antitumor activity of IFN- against Hepatocellular carcinoma (HCC), a common neoplasm worldwide that frequently develops in cirrhotic livers and may be associated with Hepatitis C or Hepatitis B viral infections. IFN- is used in the clinic to prevent and treat this cancer. However, IFN- induces several side effects, thereby limiting its benefits. By using a gene therapy approach, we compared the antitumor properties of IFN- and IFN-. BALB/c mice were inoculated with syngeneic BNL hepatoma cells, or BNL cells expressing IFN- (BNL.IFN- cells) or IFN- (BNL.IFN- cells). Despite the lack of antiproliferative activity of IFNs on BNL cells in vitro, both BNL.IFN- and BNL.IFN- cells exhibited retarded growth kinetics in vivo. Depletion of NK cells from splenocytes resulted in the inhibition of splenocyte cytotoxicity, demonstrating that NK cells are important mediators of IFN-induced antitumor responses. In addition, IFN- and to a lesser extent, IFN- enhanced immunocytotoxicity of splenocytes primed with irradiated BNL cells. This enhanced splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN- and mediated by dendritic cells. Therefore, IFN- should be considered as an alternative or additive treatment to currently existing IFN- therapy in HCC patients.
To evaluate a possible synergism in the antitumor activities of IFN- and IFN-, we tested the the effect of the use of a combination of both IFNs in the BNL model. A combination of both IFNs administered to mice can completely reject tumors in gene therapy studies and induces complete tumor remission in mice with surgically removed tumors. Therefore, combination treatment with IFN- and IFN- elicited a potent synergistic antitumor activity in the BNL model.
In an ongoing collaborative clinical study with the Department of Surgery (UMDNJ), we assessed the modulation of the IFN response in human liver disease. STAT1 activation, levels of phosphorylated STAT1, and MHC class I antigen expression were significantly downregulated in the tumor area of patient liver tissue compared to the peritumor area, suggesting a possible link between the impairment of IFN signaling and activity, and liver tumorgenesis.

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