title: Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma.
abstract: Recently discovered type III IFNs (IFN-lambda) exert their antiviral and immunomodulatory activities through a unique receptor complex composed of IFN-lambdaR1 and interleukin-10 receptor 2. To further study type III IFNs, we cloned and characterized mouse IFN-lambda ligand-receptor system. We showed that, similar to their human orthologues, mIFN-lambda2 and mIFN-lambda3 signal through the IFN-lambda 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-lambdas. We developed B16 cells constitutively expressing murine IFN-lambda2 (B16.IFN-lambda2 cells) and evaluated their tumorigenicity in syngeneic C57BL/6 mice. Although constitutive expression of mIFN-lambda2 in melanoma cells did not affect their proliferation in vitro, the growth of B16.IFN-lambda2 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-lambda2 expression. We then developed IFN-lambda-resistant B16.IFN-lambda2 cells (B16.IFN-lambda2Res cells) and showed that their tumorigenicity was also highly impaired or completely abolished similar to B16.IFN-lambda2 cells, suggesting that IFN-lambdas engage host mechanisms to inhibit melanoma growth. These in vivo experiments show the antitumor activities of IFN-lambdas and suggest their strong therapeutic potential.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Lasfar
authors.forename: Anita
authors.initials: A
authors.lastname: Lewis-Antes
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Smirnov
authors.forename: Shubha
authors.initials: S
authors.lastname: Anantha
authors.forename: Walid
authors.initials: W
authors.lastname: Abushahba
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.forename: Kenneth
authors.initials: K
authors.lastname: Reuhl
authors.forename: Harold
authors.initials: H
authors.lastname: Dickensheets
authors.forename: Faruk
authors.initials: F
authors.lastname: Sheikh
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Raveche
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kotenko
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D006224:Cricetinae; D005260:Female; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D008024:Ligands; D017471:Receptors, Interferon; D007372:Interferons