Journal Article

Antitumor activity of Type I and Type III interferons in BNL hepatoma model

Raveche, Elizabeth, Lasfar, Ahmed, Abushahba, Walid, Yuan, Yao, Balan, Murugabaskar, Castaneda, Ismael, Reuhl, Kenneth, de la Torre, Andrew, Kotenko, Sergei V

2010

Overview

Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV) infections. Type I interferon (IFN-α) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients. However, IFN-α toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently discovered type III IFN (IFN-λ) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical trials, IFN-λ treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor properties of IFN-α and IFN-λ in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma cells, or BNL cells expressing IFN-λ (BNL.IFN-λ cells) or IFN-α (BNL.IFN-α cells). Despite the lack of antiproliferative activity of IFNs on BNL cells, both BNL.IFN-λ and BNL.IFN-α 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-λ. There was also a marked NK cell infiltration in IFN-λ producing tumors. In addition, IFN-λ and, to a lesser extent, IFN-α enhanced immunocytotoxicity of splenocytes primed with irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-γ, and mediated by dendritic cells. In contrast to NK cells, isolated from spleen CD11c+ and mPDCA+ dendritic cells responded directly to IFN-λ. The antitumor activities of IFN-λ against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into the clinical use of IFN-λ to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer.

• Publisher: Berlin/Heidelberg : Springer-Verlag,Springer-Verlag,Springer,Springer Nature B.V
• Subject: Animals / Antineoplastic Agents / Antineoplastic Agents - pharmacology / Biological and medical sciences / Cancer Research / Cancer therapies / Cell Line, Tumor / Cell Proliferation / Cell Proliferation - drug effects / classification / cytology / Cytotoxicity / Cytotoxicity, Immunologic / Cytotoxicity, Immunologic - immunology / Dendritic cells / Dendritic Cells - cytology / Dendritic Cells - immunology / Dentistry / drug effects / Female / Flow Cytometry / Gastroenterology. Liver. Pancreas. Abdomen / Genes / genetics / Hepatitis B / Hepatitis B virus / Hepatitis C / Hepatitis C and B virus / Hepatitis C virus / hepatoma / Human viral diseases / Immunohistochemistry / Immunology / Immunotherapy / Infections / Infectious diseases / Interferon Type I / Interferon Type I - genetics / Interferon Type I - pharmacology / interferons / Interferons - classification / Interferons - genetics / Interferons - pharmacology / interleukin-12 / Interleukin-12 - metabolism / Killer Cells, Natural / Killer Cells, Natural - cytology / Killer Cells, Natural - immunology / Kinases / Liver cancer / Liver cirrhosis / Liver Neoplasms, Experimental / Liver Neoplasms, Experimental - immunology / Liver Neoplasms, Experimental - pathology / Liver Neoplasms, Experimental - prevention & control / Liver. Biliary tract. Portal circulation. Exocrine pancreas / Medical sciences / Medicine / Medicine & Public Health / metabolism / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / natural killer cells / Neoplasm Transplantation / Oncology / Original Article / pathology / pharmacology / Pharmacology. Drug treatments / prevention & control / Signal transduction / Spleen / Spleen - cytology / Spleen - immunology / Spleen - metabolism / STAT1 Transcription Factor / STAT1 Transcription Factor - immunology / STAT1 Transcription Factor - metabolism / Transfection / Tumors / Viral diseases / Viral hepatitis / Viruses