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

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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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Acknowledgments

We thank George Yap, Deborah Lazzarino, David Lagunoff, Lauriston Prescott and Edward Azzam for reagents, technical support and helpful suggestions. This study was supported in part by the US Public Health Services Grant RO1 AI057468 (SVK) from the NIAID, and P30 ES005022 (KR) from NIEHS for the Molecular Pathology Core. Author Statement: AL and SVK designed research; WA and AL performed research; MB, IC, AD and YY provided technical assistance; IC performed statistical analysis; WA, AD, KR, ESR, AL and SVK analyzed data; and WA, AL and SVK wrote the manuscript. AL and SVK contributed equally to this study.

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Authors and Affiliations

  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

    Walid Abushahba, Murugabaskar Balan, Ahmed Lasfar & Sergei V. Kotenko

  2. Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA

    Ismael Castaneda & Andrew de la Torre

  3. Department of Pathology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA

    Yao Yuan & Elizabeth Raveche

  4. Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA

    Kenneth Reuhl

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  1. Walid Abushahba
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  2. Murugabaskar Balan
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  3. Ismael Castaneda
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  4. Yao Yuan
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  5. Kenneth Reuhl
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  7. Andrew de la Torre
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  8. Ahmed Lasfar
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  9. Sergei V. Kotenko
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Correspondence to Ahmed Lasfar or Sergei V. Kotenko.

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Abushahba, W., Balan, M., Castaneda, I. et al. Antitumor activity of Type I and Type III interferons in BNL hepatoma model. Cancer Immunol Immunother 59, 1059–1071 (2010). https://doi.org/10.1007/s00262-010-0831-3

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