Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma
Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma
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DOI：
10.1038/gt.2008.58
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发表时间：
2008-09-01
期刊：
影响因子：
5.1
通讯作者：
Melcher, A. A.
中科院分区：
文献类型：
--
作者：
Errington, F.;White, C. L.;Melcher, A. A.
呼肠孤病毒是一种有前途的未经修饰的双链RNA（dsRNA）抗癌溶瘤病毒，其被认为特异性靶向具有活化Ras的细胞。尽管呼肠孤病毒已经在广泛的临床前模型中进行了测试，并已进入早期临床试验，但它以前尚未被测试用于治疗人类黑色素瘤。在这里，我们表明，呼肠孤病毒有效地杀死和复制在人类黑色素瘤细胞系和新鲜切除的肿瘤;瘤内注射也导致黑色素瘤在异种移植体内模型的消退。呼肠孤病毒诱导的黑色素瘤死亡被半胱天冬酶抑制阻断，并依赖于Ras/RalGEF/p38通路的成分。呼肠孤病毒黑色素瘤杀伤比化疗或放疗诱导的细胞死亡更有效，并且与化疗或放疗诱导的细胞死亡不同;感染的肿瘤细胞释放一系列炎性细胞因子和趋化因子，而IL-10分泌被废除。此外，由呼肠孤病毒感染的肿瘤细胞产生的炎症反应引起针对呼肠孤病毒抗性肿瘤细胞的旁观者毒性，并在体外激活人骨髓树突状细胞（DC）。因此，呼肠孤病毒适用于黑色素瘤的临床试验，并可能提供有用的危险信号，以逆转这种肿瘤的免疫抑制环境特征。
Reovirus is a promising unmodified double-stranded RNA (dsRNA) anti-cancer oncolytic virus, which is thought to specifically target cells with activated Ras. Although reovirus has been tested in a wide range of preclinical models and has entered early clinical trials, it has not previously been tested for the treatment of human melanoma. Here, we show that reovirus effectively kills and replicates in both human melanoma cell lines and freshly resected tumour; intratumoural injection also causes regression of melanoma in a xenograft in vivo model. Reovirus-induced melanoma death is blocked by caspase inhibition and is dependent on constituents of the Ras/RalGEF/p38 pathway. Reovirus melanoma killing is more potent than, and distinct from, chemotherapy or radiotherapy-induced cell death; a range of inflammatory cytokines and chemokines are released by infected tumour cells, while IL-10 secretion is abrogated. Furthermore, the inflammatory response generated by reovirus-infected tumour cells causes bystander toxicity against reovirus-resistant tumour cells and activates human myeloid dendritic cells (DC) in vitro. Hence, reovirus is suitable for clinical testing in melanoma, and may provide a useful danger signal to reverse the immunologically suppressive environment characteristic of this tumour.