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Growth Suppression of the Hepatocellular Carcinoma Cell Line Hepa1-6 by an Activatable Interferon Regulatory Factor-1 in Mice¹

Department of Gene Regulation and Differentiation, Gesellschaft für Biotechnologische Forschung, Braunschweig [A. K., H-J. H.]; and Department of Medicine II, University Hospital Freiburg [D. O., T. U. K., L. M., H. E. B., M. G.], Germany

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis and few therapeutic options. The aim of the study was to evaluate the potential of IFN regulatory factor-1 (IRF-1) for cytokine gene therapy of HCC using an IRF-1/human estrogen receptor fusion protein (IRF-1hER), which is reversibly activatable by ß-estradiol (E₂). IRF-1hER stably expressing murine Hepa1-6 HCC cells (HepaIRF-1hER) were characterized by ^lowMHC I, ^highCD54, and lack of MHC II, CD80, and CD86 expression. Activation of HepaIRF-1hER cells induced a ^highMHC I, ^lowMHC II, and ^highCD54 phenotype. Furthermore, they were characterized by IFN-ß secretion, decreased anchorage-independent growth in a soft agar assay, and diminished cell growth. Tumor growth in E₂-treated syngeneic C57L/J mice, but not in E₂-untreated mice, was suppressed. These E₂-treated mice were protected against rechallenge with HepaIRF-1hER and wild-type Hepa1-6 tumors even in the absence of E₂, suggesting induction of tumor specific immunity. In fact, significant CTL activity against Hepa1-6 tumors and the endogenously expressed HCC-specific self antigen -fetoprotein was observed. Antitumoral effects, however, were only partially dependent on both CD4+ and CD8+ T cells. IRF-1 treatment of mice bearing HepaIRF-1hER tumors resulted in growth arrest of tumors, and a significant survival benefit was observed in comparison to E₂-untreated mice. In conclusion, our data demonstrate that IRF-1 suppresses HCC growth through both a direct antitumor growth effect and enhanced immune cell recognition of the tumor and is a promising candidate for gene therapy of HCC.

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