Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses.

译文

选择或设计溶瘤病毒(OVs),以通过直接感染和裂解癌细胞来消除恶性肿瘤。与通过病毒感染直接裂解肿瘤的概念相反,我们观察到两个OV(水泡性口腔炎病毒(VSV)和牛痘病毒)在体内的大部分肿瘤杀伤活性是由未杀伤的肿瘤细胞的间接杀伤引起的。在施用溶瘤病毒后不久,我们观察到有限的病毒感染,与流向肿瘤内部的血流减少相一致,这与诱导肿瘤细胞凋亡有关。肿瘤的转录谱分析表明,病毒感染导致促炎基因(包括嗜中性粒细胞趋化因子CXCL1和CXCL5)的转录激活。感染组织的免疫组织化学检查显示,嗜中性粒细胞浸润与趋化因子诱导有关。在施用VSV之前,动物中性粒细胞的消耗消除了未感染的肿瘤细胞凋亡,并允许病毒在整个肿瘤中更广泛地复制和传播。综上所述,这些结果表明嗜中性粒细胞靶向募集至感染的肿瘤床增强了对恶性细胞的杀死。我们建议炎症细胞的激活可用于增强溶瘤病毒疗法的有效性,并且这种方法应影响治疗剂量的计划。

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