Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models.
Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models.
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DOI：
10.18632/oncotarget.12975
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发表时间：
2016-11-29
期刊：
影响因子：
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通讯作者：
Nair SK
中科院分区：
文献类型：
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作者：
Holl EK;Brown MC;Boczkowski D;McNamara MA;George DJ;Bigner DD;Gromeier M;Nair SK
肿瘤内接种具有肿瘤选择性细胞毒性的病毒可能会诱导癌细胞死亡，从而缩小肿瘤病变。然而，单独杀死病毒肿瘤细胞不太可能产生有意义的、持久的临床反应，因为临床上合适的“溶瘤”病毒被严重减毒，并且它们的传播和繁殖受到宿主免疫的阻碍。因此，在这种情况下，更有利的事件是对瘤内病毒施用的先天抗病毒反应，特别是对于招募持久的适应性免疫效应反应。它可能是一把双刃剑，因为先天免疫激活可能会尽早消除受感染的肿瘤细胞，拦截病毒传播并阻止任何有意义的治疗反应。由于肿瘤基质不寻常的组成/组织特性，肿瘤对病毒感染的先天反应可能与非恶性靶组织的反应非常不同。在这项工作中，我们报告了在乳腺癌和前列腺癌的两种小鼠异种移植模型中对溶瘤脊髓灰质炎病毒重组体 PVSRIPO 的先天免疫反应的研究。我们的观察表明，病毒在受感染的肿瘤中短期存在，而病毒恢复则表明肿瘤内传播和持续性适度。然而，强大的先天炎症反应与趋化因子诱导和骨髓细胞浸润肿瘤同时发生，有趣的是，肿瘤以中性粒细胞为主。 PVSRIPO 肿瘤感染及其引发的先天反应的综合作用在两种模型中均使肿瘤显着消退。
Intratumoral inoculation of viruses with tumor-selective cytotoxicity may induce cancer cell death and, thereby, shrink neoplastic lesions. It is unlikely, however, that viral tumor cell killing alone could produce meaningful, durable clinical responses, as clinically suitable ‘oncolytic’ viruses are severely attenuated and their spread and propagation are opposed by host immunity. Thus, a more propitious event in this context is the innate antiviral response to intratumoral virus administration, in particular for recruiting durable adaptive immune effector responses. It may represent a double-edged sword, as innate immune activation may eliminate infected tumor cells early, intercept viral spread and block any meaningful therapeutic response. The innate response to viral infection of tumors may be very different from that in non-malignant target tissues, owing to the unusual composition/tissue properties of tumor stroma. In this work, we report investigations of the innate immune response to the oncolytic poliovirus recombinant, PVSRIPO, in two mouse xenotransplantation models for breast and prostate cancer. Our observations indicate short-term virus persistence in infected tumors and virus recovery indicative of modest intratumoral propagation and persistence. Yet, a powerful innate inflammatory response coincided with chemokine induction and myeloid cell infiltration into tumors that was, interestingly, dominated by neutrophils. The combined effect of PVSRIPO tumor infection and the innate response it elicits was significant tumor regression in both models.