title: Antitumor activity of type I and type III interferons in BNL hepatoma model.
abstract: Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV) infections. Type I interferon (IFN-alpha) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients. However, IFN-alpha toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently discovered type III IFN (IFN-lambda) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical trials, IFN-lambda treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor properties of IFN-alpha and IFN-lambda in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma cells, or BNL cells expressing IFN-lambda (BNL.IFN-lambda cells) or IFN-alpha (BNL.IFN-alpha cells). Despite the lack of antiproliferative activity of IFNs on BNL cells, both BNL.IFN-lambda and BNL.IFN-alpha cells displayed retarded growth kinetics in vivo. Depletion of NK cells from splenocytes inhibited splenocyte-mediated cytotoxicity, demonstrating that NK cells play a role in IFN-induced antitumor responses. However, isolated NK cells did not respond directly to IFN-lambda. There was also a marked NK cell infiltration in IFN-lambda producing tumors. In addition, IFN-lambda and, to a lesser extent, IFN-alpha enhanced immunocytotoxicity of splenocytes primed with irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-gamma, and mediated by dendritic cells. In contrast to NK cells, isolated from spleen CD11c+ and mPDCA+ dendritic cells responded directly to IFN-lambda. The antitumor activities of IFN-lambda against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into the clinical use of IFN-lambda to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology and University Hospital Cancer Center, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors.forename: Walid
authors.initials: W
authors.lastname: Abushahba
authors.forename: Murugabaskar
authors.initials: M
authors.lastname: Balan
authors.forename: Ismael
authors.initials: I
authors.lastname: Castaneda
authors.forename: Yao
authors.initials: Y
authors.lastname: Yuan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Reuhl
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Raveche
authors.forename: Andrew
authors.initials: A
authors.lastname: de la Torre
authors.forename: Ahmed
authors.initials: A
authors.lastname: Lasfar
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kotenko
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000235:genetics / Q000494:pharmacology*; D007372:Interferons / Q000145:classification / Q000235:genetics / Q000494:pharmacology*; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D007370:Interferon Type I; D050794:STAT1 Transcription Factor; D018664:Interleukin-12; D007372:Interferons