Interferon-γ induces regression of epithelial cell carcinoma:: critical roles of IRF-1 and ICSBP transcription factors

We have developed an epithelial cell carcinoma model for studying efficacy of IFN gamma gene therapy and have identified components of IFN gamma-signaling pathway responsible for its direct anti-tumor actions. The tumor results from ectopic expression of SV40 Large T-Antigen ( SV40 T-Ag) oncogene in lens of transgenic mouse ( alpha T3) and complete regression of the tumor is induced by targeting expression of IFN gamma into malignant lens cells. In. ammatory cells are absent in lens of aT3 or DT ( co-expressing IFN gamma and SV40-T-Antigen) mice and the transformed lens cells are non-immunogenic, suggesting non- involvement of immunologic cells. We show that IFN gamma has direct growth-inhibitory effects on tumor cells, induces death of tumor cells by apoptosis and that these effects are mediated by two transcription factors, IRF-1 ( interferon-regulatory factor-1) and ICSBP ( interferon-consensus sequence-binding protein) induced by IFN gamma. Furthermore, stable transfection with ICSBP or IRF-1 construct inhibits lens carcinoma cell growth by upregulating Caspase-1, p21(WAF1) and p27 expression. In contrast, tumor progression in aT3 lens correlates with inhibition of IRF-1 and ICSBP expression. Our results suggest that IFN gamma gene therapy maybe effective in malignant diseases for which DNA tumor viruses are etiologic agents and that antitumor actions of IRF-1/ICSBP can be exploited therapeutically to circumvent adverse clinical effects associated with IFN therapy.