Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
Nat Commun. 2013;4:1974. doi: 10.1038/ncomms2974.
Oncolytic viruses are complex biological agents that interact at multiple levels with both tumour and normal tissues. Antiviral pathways induced by interferon are known to have a critical role in determining tumour cell sensitivity and normal cell resistance to infection with oncolytic viruses. Here we pursue a synthetic biology approach to identify methods that enhance antitumour activity of oncolytic viruses through suppression of interferon signalling. On the basis of the mathematical analysis of multiple strategies, we hypothesize that a positive feedback loop, established by virus-mediated expression of a soluble interferon-binding decoy receptor, increases tumour cytotoxicity without compromising normal cells. Oncolytic rhabdoviruses engineered to express a secreted interferon antagonist have improved oncolytic potential in cellular cancer models, and display improved therapeutic potential in tumour-bearing mice. Our results demonstrate the potential of this methodology in evaluating potential caveats of viral immune-evasion strategies and improving the design oncolytic viruses.
溶瘤病毒是一种复杂的生物制剂，它在多个层面上与肿瘤和正常组织相互作用。干扰素诱导的抗病毒途径被认为在决定肿瘤细胞对溶瘤病毒感染的敏感性和正常细胞的抗性方面起着关键作用。在这里，我们采用合成生物学的方法来确定通过抑制干扰素信号来增强溶瘤病毒抗肿瘤活性的方法。基于对多种策略的数学分析，我们假设通过病毒介导表达可溶性干扰素结合诱饵受体来建立正反馈回路，可以在不损害正常细胞的情况下增加肿瘤细胞的细胞毒性。工程改造表达分泌型干扰素拮抗剂的溶瘤弹状病毒在细胞癌症模型中提高了溶瘤潜力，并在荷瘤小鼠中显示出了改善的治疗潜力。我们的研究结果证明了该方法在评估病毒免疫逃逸策略的潜在缺陷和改进溶瘤病毒设计方面的潜力。
