Department of Neurosurgery.
Department of Molecular Genetics and Microbiology.
Annu Rev Med. 2018 Jan 29;69:289-299. doi: 10.1146/annurev-med-050715-104655.
Mechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of eminent relevance to cancer immunotherapy. "Oncolytic" viruses, naturally existing or genetically engineered viral agents with cell type-specific propagation in malignant cells, were ostensibly conceived for their tumor cytotoxic properties. Yet, their true therapeutic value may rest in their ability to provoke antiviral signals that engage antitumor immune responses within the immunosuppressive tumor microenvironment. Coopting oncolytic viral agents to instigate antitumor immunity is not an easy feat. In the course of coevolution with their hosts, viruses have acquired sophisticated strategies to block inflammatory signals, intercept innate antiviral interferon responses, and prevent antiviral effector responses, e.g., by interfering with antigen presentation and T cell costimulation. The resulting struggle of host innate inflammatory and antiviral responses versus viral immune evasion and suppression determines the potential for antitumor immunity to occur. Moreover, paradigms of early host:virus interaction established in normal immunocompetent organisms may not hold in the profoundly immunosuppressive tumor microenvironment. In this review, we explain the mechanisms of recombinant nonpathogenic poliovirus, PVSRIPO, which is currently in phase I clinical trials against recurrent glioblastoma. We focus on an unusual host:virus relationship defined by the simple and cytotoxic replication strategy of poliovirus, which generates inflammatory perturbations conducive to tumor antigen-specific immune priming.
激发抗病毒免疫的机制是一种天然的宿主对病毒病原体挑战的反应，与癌症免疫疗法密切相关。“溶瘤”病毒是指在恶性细胞中具有特定细胞类型增殖能力的天然存在或基因工程病毒制剂，最初被认为具有肿瘤细胞毒性作用。然而，它们的真正治疗价值可能在于它们能够引发抗病毒信号，从而在免疫抑制性肿瘤微环境中引发抗肿瘤免疫反应。利用溶瘤病毒制剂来引发抗肿瘤免疫并不是一件容易的事。在与宿主共同进化的过程中，病毒已经获得了复杂的策略来阻断炎症信号、拦截先天抗病毒干扰素反应，并阻止抗病毒效应反应，例如通过干扰抗原呈递和 T 细胞共刺激。宿主先天炎症和抗病毒反应与病毒免疫逃逸和抑制之间的斗争决定了发生抗肿瘤免疫的潜力。此外，在正常免疫功能正常的机体中建立的早期宿主：病毒相互作用的范例在免疫抑制性极强的肿瘤微环境中可能并不成立。在这篇综述中，我们解释了目前正在针对复发性胶质母细胞瘤进行 I 期临床试验的重组非致病性脊髓灰质炎病毒（PVSRIPO）的机制。我们重点介绍了一种由脊髓灰质炎病毒简单而细胞毒性的复制策略定义的不寻常的宿主：病毒关系，这种关系产生了有利于肿瘤抗原特异性免疫启动的炎症扰动。
