Kröger A, Ortmann D, Krohne T U, Mohr L, Blum H E, Hauser H, Geissler M
Department of Gene Regulation and Differentiation, Gesellschaft für Biotechnologische Forschung, Freiburg, Germany.
Cancer Res. 2001 Mar 15;61(6):2609-17.
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 beta-estradiol (E2). IRF-1hER stably expressing murine Hepa1-6 HCC cells (HepaIRF-1hER) were characterized by lowMHC 1, 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-beta 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 alpha-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.
肝细胞癌（HCC）是一种高度恶性的肿瘤，预后较差且治疗选择有限。本研究的目的是评估干扰素调节因子-1（IRF-1）通过一种可被β-雌二醇（E2）可逆激活的IRF-1/人雌激素受体融合蛋白（IRF-1hER）用于HCC细胞因子基因治疗的潜力。稳定表达IRF-1hER的小鼠Hepa1-6 HCC细胞（HepaIRF-1hER）的特征为低MHC 1、高CD54，且缺乏MHC II、CD80和CD86表达。HepaIRF-1hER细胞的激活诱导了高MHC I、低MHC II和高CD54表型。此外，它们的特征还包括分泌IFN-β、在软琼脂试验中锚定非依赖性生长减少以及细胞生长减弱。E2处理的同基因C-57L/J小鼠中的肿瘤生长受到抑制，而未用E2处理的小鼠则不然。这些经E2处理的小鼠即使在没有E2的情况下也能免受HepaIRF-1hER和野生型Hepa1-6肿瘤的再次攻击，提示诱导了肿瘤特异性免疫。事实上，观察到针对Hepa1-6肿瘤和内源性表达的HCC特异性自身抗原甲胎蛋白的显著CTL活性。然而，抗肿瘤作用仅部分依赖于CD4+和CD8+ T细胞。用IRF-1处理携带HepaIRF-1hER肿瘤的小鼠导致肿瘤生长停滞，与未用E2处理的小鼠相比，观察到显著的生存获益。总之，我们的数据表明，IRF-1通过直接的抗肿瘤生长作用和增强免疫细胞对肿瘤的识别来抑制HCC生长，是HCC基因治疗的一个有前景的候选者。
