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Characterization of the Mouse IFN- Ligand-Receptor System: IFN-s Exhibit Antitumor Activity against B16 Melanoma

Departments of ¹ Biochemistry and Molecular Biology and ² Pathology and Laboratory Medicine, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey; ³ Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey; and ⁴ Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland

Requests for reprints: Sergei V. Kotenko, Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry-New Jersey Medical School, Newark, NJ 07103. Phone: 973-972-3134; Fax: 973-972-5594; E-mail: kotenkse{at}umdnj.edu.

Recently discovered type III IFNs (IFN-) exert their antiviral and immunomodulatory activities through a unique receptor complex composed of IFN-R1 and interleukin-10 receptor 2. To further study type III IFNs, we cloned and characterized mouse IFN- ligand-receptor system. We showed that, similar to their human orthologues, mIFN-2 and mIFN-3 signal through the IFN- receptor complex, activate IFN stimulated gene factor 3, and are capable of inducing antiviral protection and MHC class I antigen expression in several cell types including B16 melanoma cells. We then used the murine B16 melanoma model to investigate the potential antitumor activities of IFN-s. We developed B16 cells constitutively expressing murine IFN-2 (B16.IFN-2 cells) and evaluated their tumorigenicity in syngeneic C57BL/6 mice. Although constitutive expression of mIFN-2 in melanoma cells did not affect their proliferation in vitro, the growth of B16.IFN-2 cells, when injected s.c. into mice, was either retarded or completely prevented. We found that rejection of the modified tumor cells correlated with their level of IFN-2 expression. We then developed IFN--resistant B16.IFN-2 cells (B16.IFN-2Res cells) and showed that their tumorigenicity was also highly impaired or completely abolished similar to B16.IFN-2 cells, suggesting that IFN-s engage host mechanisms to inhibit melanoma growth. These in vivo experiments show the antitumor activities of IFN-s and suggest their strong therapeutic potential. (Cancer Res 2006; 66(8): 4468-77)

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