Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: role of type I interferon signaling.
Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: role of type I interferon signaling.
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DOI：
10.1016/j.virol.2012.11.014
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发表时间：
2013-02-05
期刊：
影响因子：
3.7
通讯作者：
Grdzelishvili VZ
中科院分区：
文献类型：
--
作者：
Moerdyk-Schauwecker M;Shah NR;Murphy AM;Hastie E;Mukherjee P;Grdzelishvili VZ
溶瘤病毒（OV）疗法利用常见的癌症特征，如有缺陷的I型干扰素（IFN）信号传导，优先感染和杀死癌细胞的病毒。我们最近的研究（，J. Virol.，八十六：3073-87）发现人胰腺导管腺癌（PDA）细胞在其对水泡性口炎病毒（VSV）的容许性方面是高度异质的，并表明至少一些抗性细胞系保留功能性I型IFN应答。在这里，我们通过分析一组11个人PDA细胞系中与I型IFN途径相关的33个基因的表达，研究了细胞对溶瘤VSV重组体VSV-ΔM51-GFP感染的反应。尽管所有细胞系都能感受到VSV-ΔM51-GFP的感染，并且IFN-α和IFN-β表达最活跃，但只有抗性细胞系显示IFN刺激的抗病毒基因MxA和OAS的组成型高水平表达。JAK/STAT信号传导的抑制降低了MxA和OAS的水平，并增加了VSV感染、复制和溶瘤作用，进一步暗示了IFN应答与耐药性有关。与VSV不同，牛痘和单纯疱疹病毒的感染性和对PDA细胞的杀伤独立于I型IFN信号传导谱，可能是因为这两种病毒更好地装备以逃避I型IFN应答。我们的研究表明PDA细胞I型IFN信号传导状态的异质性，并表明MxA和OAS作为PDA对VSV和其他对I型IFN反应敏感的OV的抗性的潜在生物标志物。
Oncolytic virus (OV) therapy takes advantage of common cancer characteristics, such as defective type I interferon (IFN) signaling, to preferentially infect and kill cancer cells with viruses. Our recent study (, J. Virol., 86: 3073-87) found human pancreatic ductal adenocarcinoma (PDA) cells were highly heterogeneous in their permissiveness to vesicular stomatitis virus (VSV) and suggested at least some resistant cell lines retained functional type I IFN responses. Here we examine cellular responses to infection by the oncolytic VSV recombinant VSV-ΔM51-GFP by analyzing a panel of 11 human PDA cell lines for expression of 33 genes associated with type I IFN pathways. Although all cell lines sensed infection by VSV-ΔM51-GFP and most activated IFN-α and β expression, only resistant cell lines displayed constitutive high-level expression of the IFN-stimulated antiviral genes MxA and OAS. Inhibition of JAK/STAT signaling decreased levels of MxA and OAS and increased VSV infection, replication and oncolysis, further implicating IFN responses in resistance. Unlike VSV, vaccinia and herpes simplex virus infectivity and killing of PDA cells was independent of the type I IFN signaling profile, possibly because these two viruses are better equipped to evade type I IFN responses. Our study demonstrates heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other OVs sensitive to type I IFN responses.
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