Epigenetic Silencing of IRF7 and/or IRF5 in Lung Cancer Cells Leads to Increased Sensitivity to Oncolytic Viruses

Defective IFN signaling results in loss of innate immunity and sensitizes cells to enhanced cytolytic killing after Vesticular Stomatitis Virus (VSV) infection. Examination of the innate immunity status of normal human bronchial epithelial cells Beas2B and 7 lung cancer cells revealed that the abrogation of IFN signaling in cancer cells is associated with greater sensitivity to VSV infection. The disruption of the IFN pathway in lung cancer cell lines and primary tumor tissues is caused by epigenetic silencing of critical interferon responsive transcription factors IRF7 and/or IRF5. Although 5-aza-2′-deoxycytidine treatment fails to reactivate IRF7 and IRF5 expression or protect cells from VSV infection, manipulating IFN signaling by altering IRF expression changes the viral susceptibility of these cells. Lung cancer cells can be partially protected from viral killing using IRF5+IRF7 overexpression, whereas IFN pathway disruption by transfection of siRNAs to IRF5+IRF7 increases cells' vulnerability to viral infection. Therefore, IRF5 and IRF7 are key transcription factors in IFN pathway that determine viral sensitivity of lung cancer cells; the epigenetically impaired IFN pathway in lung cancer tissues provides potential biomarkers for successful selective killing of cancer cells by oncolytic viral therapy.

功能缺陷的干扰素（Interferon, IFN）信号通路会导致先天免疫丧失，并使细胞在感染水泡性口炎病毒（Vesicular Stomatitis Virus，VSV）后更易发生溶细胞杀伤。本研究对正常人支气管上皮细胞Beas2B与7株肺癌细胞的先天免疫状态进行检测后发现，癌细胞中IFN信号通路的阻断与细胞对VSV感染的敏感性增强相关。肺癌细胞系及原发性肿瘤组织中IFN通路的破坏，由关键干扰素应答转录因子IRF7和/或IRF5的表观遗传沉默所介导。尽管5-氮杂-2'-脱氧胞苷处理无法重新激活IRF7与IRF5的表达，也不能保护细胞免受VSV感染，但通过调控IRF的表达来改变IFN信号通路，可改变这些细胞的病毒易感性。过表达IRF5与IRF7可部分保护肺癌细胞免受病毒杀伤；而通过转染靶向IRF5和IRF7的小干扰RNA（small interfering RNAs，siRNAs）破坏IFN通路，则会增强细胞对病毒感染的易感性。综上，IRF5与IRF7是IFN通路中决定肺癌细胞病毒敏感性的关键转录因子；肺癌组织中表观遗传受损的IFN通路，可为溶瘤病毒疗法精准杀伤癌细胞提供潜在的生物标志物。