Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death
Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death
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DOI：
10.1002/ijc.29202
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发表时间：
2015-03-01
影响因子：
6.4
通讯作者：
Van Gool, Stefaan W.
中科院分区：
文献类型：
--
作者：
Koks, Carolien A.;Garg, Abhishek D.;Van Gool, Stefaan W.
多种天然溶瘤病毒的溶瘤特征已在多形性胶质母细胞瘤细胞系和异种移植模型中显示出来。然而，缺乏对免疫活性动物的原位神经胶质瘤研究。在这里，我们在原位同基因小鼠 GL261 模型中研究了新城疫病毒 (NDV)。肿瘤诱导7天后，小鼠瘤内注射NDV。治疗显着延长了中位生存期，50% 的动物表现出长期生存。我们证明了 NDV 感染后 GL261 细胞中的免疫原性细胞死亡 (ICD) 诱导，包括钙网蛋白表面暴露、HMGB1 释放和 PMEL17 癌症抗原表达增加。独特的是，我们发现不存在分泌的 ATP。 NDV 诱导的 ICD 独立于 caspase 信号传导而发生，并被 Necrostatin-1 阻断，表明坏死性凋亡的影响。 GL261 细胞 NDV 感染后的自噬诱导也得到证实。在体内，在 NDV 治疗的肿瘤中观察到 IFN-(+) T 细胞的浸润增加，同时骨髓源性抑制细胞的积累减少。在免疫缺陷 Rag2(-/-) 小鼠和 CD8(+) T 细胞耗尽的动物中，功能性适应性免疫系统的重要性得到了证明，其中 NDV 稍微延长了存活时间，但未能诱导长期治愈。在NDV治疗后长期存活的小鼠中，用GL261细胞或LLC细胞进行继发性肿瘤诱导，证明ND病毒疗法可诱导长期的肿瘤特异性免疫记忆反应。我们首次描述了 NDV 对 GL261 肿瘤的治疗活性，并在原位小鼠模型中得到证实。治疗效果依赖于肿瘤细胞中 ICD 的诱导，从而引发适应性抗肿瘤免疫。有什么新鲜事？多形性胶质母细胞瘤的预后特别严峻。一种潜在的治疗方法是溶瘤病毒疗法（OVT），它依赖于特异性感染和裂解肿瘤细胞的病毒。在这项研究中，作者发现，神经胶质瘤注射新城疫病毒（NDV）的小鼠的存活时间明显长于对照组。许多研究人员认为，为了使 OVT 发挥作用，必须抑制免疫系统。然而，在这里，新城疫病毒实际上刺激了免疫原性细胞死亡（ICD）和坏死性凋亡（而不是细胞凋亡）。因此，OVT 与刺激免疫反应的疗法相结合可能是一种有前途的治疗方法。
The oncolytic features of several naturally oncolytic viruses have been shown on Glioblastoma Multiforme cell lines and in xenotransplant models. However, orthotopic glioma studies in immunocompetent animals are lacking. Here we investigated Newcastle disease virus (NDV) in the orthotopic, syngeneic murine GL261 model. Seven days after tumor induction, mice received NDV intratumorally. Treatment significantly prolonged median survival and 50% of animals showed long-term survival. We demonstrated immunogenic cell death (ICD) induction in GL261 cells after NDV infection, comprising calreticulin surface exposure, release of HMGB1 and increased PMEL17 cancer antigen expression. Uniquely, we found absence of secreted ATP. NDV-induced ICD occurred independently of caspase signaling and was blocked by Necrostatin-1, suggesting the contribution of necroptosis. Autophagy induction following NDV infection of GL261 cells was demonstrated as well. In vivo, elevated infiltration of IFN-(+) T cells was observed in NDV-treated tumors, along with reduced accumulation of myeloid derived suppressor cells. The importance of a functional adaptive immune system in this paradigm was demonstrated in immunodeficient Rag2(-/-) mice and in CD8(+) T cell depleted animals, where NDV slightly prolonged survival, but failed to induce long-term cure. Secondary tumor induction with GL261 cells or LLC cells in mice surviving long-term after NDV treatment, demonstrated the induction of a long-term, tumor-specific immunological memory response by ND virotherapy. For the first time, we describe the therapeutic activity of NDV against GL261 tumors, evidenced in an orthotopic mouse model. The therapeutic effect relies on the induction of ICD in the tumor cells, which primes adaptive antitumor immunity.What's new? Glioblastoma multiforme has a particularly grim prognosis. One potential treatment is oncolytic virotherapy (OVT), which relies on viruses that specifically infect and lyse tumor cells. In this study, the authors found that mice whose gliomas were injected with Newcastle-disease virus (NDV) survived significantly longer than controls. Many researchers have assumed that, in order for OVT to work, the immune system must be suppressed. Here, however, NDV actually stimulated immunogenic cell death (ICD) and necroptosis (rather than apoptosis). OVT may thus be a promising therapeutic approach in combination with therapies that stimulate the immune response.