Antitumor activity of Type I and Type III interferons in BNL hepatoma model |
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Authors: | Walid Abushahba Murugabaskar Balan Ismael Castaneda Yao Yuan Kenneth Reuhl Elizabeth Raveche Andrew de la Torre Ahmed Lasfar Sergei V Kotenko |
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Institution: | (1) Department of Biochemistry and Molecular Biology and University Hospital Cancer Center, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 205 South Orange Ave, Newark, NJ 07103, USA;(2) Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA;(3) Department of Pathology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA;(4) Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA; |
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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. |
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