Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow
Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow
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DOI：
10.1038/sj.mt.6300215
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发表时间：
2007-09-01
影响因子：
12.4
通讯作者：
Bell, John C.
中科院分区：
文献类型：
--
作者：
Breitbach, Caroline J.;Paterson, Jennifer M.;Bell, John C.
选择或设计溶瘤病毒（OV）以通过直接感染和裂解癌细胞来消除恶性肿瘤。与病毒感染直接溶解肿瘤的概念相反，我们观察到两种OVs（水泡性口炎病毒（VSV）和牛痘病毒）的体内肿瘤杀伤活性的很大一部分是由间接杀伤未感染的肿瘤细胞引起的。在施用溶瘤病毒后不久，我们观察到有限的病毒感染，与肿瘤内部的血流损失一致，这与肿瘤细胞中的细胞凋亡诱导相关。肿瘤的转录谱显示，病毒感染导致促炎基因（包括中性粒细胞趋化因子CXCL 1和CXCL 5）的显著转录激活。感染肿瘤的免疫组织化学检查显示与趋化因子诱导相关的中性粒细胞浸润。在VSV给药之前，动物中性粒细胞的耗竭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的复制和传播。总的来说，这些结果表明，嗜中性粒细胞靶向募集到感染的肿瘤床增强了对恶性细胞的杀伤。我们建议，激活炎症细胞可用于增强溶瘤病毒治疗的有效性，这种方法应该影响治疗剂量的规划。
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.