Antitumor activity of Type I and Type III interferons in BNL hepatoma model
- 9 March 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 59 (7), 1059-1071
- https://doi.org/10.1007/s00262-010-0831-3
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-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.Keywords
This publication has 63 references indexed in Scilit:
- Genetic variation in IL28B and spontaneous clearance of hepatitis C virusNature, 2009
- Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunityBlood, 2009
- Intranasal Administration of Alpha Interferon Reduces Seasonal Influenza A Virus Morbidity in FerretsJournal of Virology, 2009
- IFN-Lambda (IFN-λ) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In VivoPLoS Pathogens, 2008
- Liver Transplantation for Hepatocellular CarcinomaAnnals of Surgical Oncology, 2008
- Inhibition of type I and type III interferons by a secreted glycoprotein from Yaba-like disease virusProceedings of the National Academy of Sciences of the United States of America, 2007
- A Randomized, Controlled Trial of Postoperative Adjuvant Interferon Therapy After Resection of Hepatocellular CarcinomaAnnals of Surgery, 2007
- Hepatocellular Carcinoma: Molecular Biology and TherapySeminars in Oncology, 2006
- Hepatocellular carcinoma pathogenesis: from genes to environmentNature Reviews Cancer, 2006
- Lambda Interferon (IFN-λ), a Type III IFN, Is Induced by Viruses and IFNs and Displays Potent Antiviral Activity against Select Virus Infections In VivoJournal of Virology, 2006