Antitumor activity of IFN-ℷ in murine tumor models
Antitumor activity of IFN-ℷ in murine tumor models
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DOI：
10.4049/jimmunol.176.12.7686
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发表时间：
2006-06-15
影响因子：
4.4
通讯作者：
Murakami, Takashi
中科院分区：
文献类型：
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作者：
Sato, Atsuko;Ohtsuki, Mamitaro;Murakami, Takashi
已发现IFN-λ 1、IFN-λ 2和IFN-λ 3是II类细胞因子家族的最新成员，并显示具有抗病毒活性。用小鼠IFN-λ转导小鼠B16黑色素瘤和Colon 26癌细胞以确定IFN-λ是否具有抗肿瘤活性。IFN-λ过表达诱导B16细胞表面MHC I类分子表达和Fas/CD 95 Ag表达，诱导显著的caspase-3/7活性，并增加p21（waf 1/Cip 1）和去磷酸化Rb（Ser（780））。肿瘤细胞系中IFN-λ表达显著抑制s.c.体内转移瘤形成率与mock转染组相比有显著性差异（P < 0.05）。此外，IFN-λ表达诱导淋巴细胞浸润，Ab介导的免疫细胞耗竭试验表明NK细胞对IFN-λ介导的肿瘤生长抑制至关重要。流体动力学注射IFN-λ cDNA成功靶向结肠26细胞的肝转移灶，并适度降低肿瘤小鼠的死亡率。肝脏中IFN-λ过表达增加了NK/NKT细胞，增强了它们的肿瘤杀伤活性，并提示了先天免疫应答的激活。因此，IFN-λ通过先天免疫应答诱导肿瘤细胞凋亡和NK细胞介导的免疫肿瘤破坏。这些发现表明，局部递送IFN-λ可能被证明是人类恶性肿瘤临床治疗中有用的预防策略。
IFN-lambda 1, -lambda 2 and -lambda 3 have been discovered as the latest members of the class II cytokine family and shown to possess antiviral activity. Murine B16 melanoma and Colon26 cancer cells were transduced with mouse IFN-lambda to determine whether IFN-lambda possesses antitumor activity. Overexpression of IFN-lambda induced cell surface MHC class I expression and Fas/CD95 Ag, induced significant caspase-3/7 activity, and increased p21(waf1/Cip1) and dephosphorylated Rb (Ser(780)) in B16 cells in vitro. IFN-lambda expression in tumor cell lines markedly inhibited s.c. and metastatic tumor formation in vivo compared with mock transfections (P < 0.05). Moreover, IFN-lambda expression induced lymphocytic infiltrates, and an Ab-mediated immune cell depletion assay showed that NK cells were critical to IFN-lambda-mediatid tumor growth inhibition. Hydrodynamic injection of IFN-lambda cDNA successfully targeted liver metastatic foci of Colon26 cells, and moderately decreased the mortality of mice with tumors. IFN-lambda overexpression in the liver increased NK/NKT cells and enhanced their tumor-killing activity, and suggested the activation of innate immune responses. Thus, IFN-lambda induced both tumor apoptosis and NK cell-mediated immunological tumor destruction through innate immune responses. These findings suggested that local delivery of IFN-lambda might prove a useful adjunctive strategy in the clinical treatment of human malignancies.