title: IFN regulatory factor-1 gene transfer into an aggressive, nonimmunogenic sarcoma suppresses the malignant phenotype and enhances immunogenicity in syngeneic mice.
abstract: IFN-gamma has a direct antitumor effect on many tumor cell lines mediated through the IFN-gammaR. One effect of IFN-gamma is to induce the nuclear transcription factor IFN regulatory factor-1 (IRF-1), which may function as a tumor suppressor. In this study, mouse IRF-1 cDNA under a high constitutive expression promoter was transfected into the highly aggressive, nonimmunogenic MCA 101 murine sarcoma. Clones were obtained by G418 selection and screened for IRF-1 mRNA expression by reverse transcriptase-PCR (RT-PCR). High expression clones had high levels of two MHC class I proteins (H-2Kb and H-2Db) on the cell surface that correlated with increased levels of class I mRNA by RT-PCR. Furthermore, these clones also had increased levels of MHC class II protein (I-Ab), which correlated with increased levels of one subunit of class II mRNA by RT-PCR. IRF-1-expressing clones had markedly diminished cell growth in vitro and decreased anchorage-independent growth in a soft agar assay. These clones also demonstrated markedly prolonged tumor latency and slowed growth in syngeneic C57BL/6 mice. IRF-1 gene-transfected cells had shortened tumor latency and formed faster growing tumors in gamma-irradiated immunodeficient mice compared with results in immunocompetent mice. Mice immunized with IRF-1-transfected cells were protected against subsequent challenge with IRF-1 transfected cells and also demonstrated greater tumor latency and slower tumor growth against subsequent challenge with untransfected cells compared with mice immunized with empty vector-transfected cells. These studies demonstrate a tumor suppressor effect of IRF-1, which acts in vivo through both partial reversion of the malignant phenotype and enhanced immune recognition and may play a role in the antitumor effects of IFN-gamma.
authors.affiliation: Laboratory of Biological Therapy, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Yim
authors.forename: S J
authors.initials: SJ
authors.lastname: Wu
authors.forename: M J
authors.initials: MJ
authors.lastname: Casey
authors.forename: J A
authors.initials: JA
authors.lastname: Norton
authors.forename: G M
authors.initials: GM
authors.lastname: Doherty
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000502:physiology / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D006183:H-2 Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007167:Immunotherapy; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000502:physiology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D014157:Transcription Factors / Q000502:physiology / Q000627:therapeutic use
chemical_list: D004268:DNA-Binding Proteins; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D007371:Interferon-gamma