Innate Immune Defense Defines Susceptibility of Sarcoma Cells to Measles Vaccine Virus-Based Oncolysis
Innate Immune Defense Defines Susceptibility of Sarcoma Cells to Measles Vaccine Virus-Based Oncolysis
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DOI：
10.1128/jvi.02106-12
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发表时间：
2013-03-01
影响因子：
5.4
通讯作者：
Lauer, Ulrich M.
中科院分区：
文献类型：
--
作者：
Berchtold, Susanne;Lampe, Johanna;Lauer, Ulrich M.
麻疹疫苗病毒（MeV）的溶瘤潜力已在几种肿瘤实体中得到证实。在这里，我们调查了八个肉瘤细胞系的敏感性MeV介导的溶瘤，发现五个是敏感的，而三个被证明是耐药的。在MeV抗性细胞系中，我们经常观察到病毒复制的抑制沿着细胞内病毒敏感分子RIG-1和干扰素（IFN）刺激的基因IFIT 1的强烈上调。不仅IFIT 1的表达，而且IFN-刺激的Stat 1的磷酸化迅速发生，并发现随着时间的推移是持久的。相比之下，易感细胞系显示出更弱，延迟，或完全缺失IFIT 1的表达，以及延迟或仅瞬时磷酸化的Stat 1，而外源刺激β干扰素（IFN-β）导致相当深刻的激活Stat 1和IFIT 1的表达在所有细胞系。用IFN-β预处理使三种易感细胞系对MeV介导的溶瘤作用更具抗性。这些数据表明，在先天免疫防御的差异往往占不同程度的敏感性肉瘤细胞株MeV介导的溶瘤。从治疗的角度来看，我们能够克服抵抗MeV通过增加感染复数（MOI），并通过添加前药5-氟胞嘧啶（FC），从而利用自杀基因功能的病毒治疗载体MeV-SCD武装SCD融合蛋白，其中包括酵母胞嘧啶脱氨酶和酵母尿嘧啶磷酸核糖转移酶。
The oncolytic potential of measles vaccine virus (MeV) has been demonstrated in several tumor entities. Here, we investigated the susceptibility of eight sarcoma cell lines to MeV-mediated oncolysis and found five to be susceptible, whereas three proved to be resistant. In the MeV-resistant cell lines, we often observed an inhibition of viral replication along with a strong upregulation of the intracellular virus-sensing molecule RIG-I and of the interferon (IFN)-stimulated gene IFIT1. Not only expression of IFIT1 but also phosphorylation of IFN-stimulated Stat1 took place rapidly and were found to be persistent over time. In contrast, susceptible cell lines showed a much weaker, delayed, or completely missing expression of IFIT1 as well as a delayed or only transient phosphorylation of Stat1, whereas exogenic stimulation with beta interferon (IFN-beta) resulted in a comparable profound activation of Stat1 and expression of IFIT1 in all cell lines. Pretreatment with IFN-beta rendered three of the susceptible cell lines more resistant to MeV-mediated oncolysis. These data suggest that differences in the innate immune defense often account for different degrees of susceptibility of sarcoma cell lines to MeV-mediated oncolysis. From a therapeutic perspective, we were able to overcome resistance to MeV by increasing the multiplicity of infection (MOI) and by addition of the prodrug 5-fluorocytosine (FC), thereby exploiting the suicide gene function of virotherapeutic vector MeV-SCD armed with the SCD fusion protein, which consists of yeast cytosine deaminase and yeast uracil phosphoribosyltransferase.