The Research Institute at Nationwide Children's Hospital Center for Childhood Cancer and Blood Disorders, The Ohio State University, Columbus, Ohio.
Nationwide Children's Hospital, Department of Pediatrics, Division of Pediatric Infectious Diseases, The Ohio State University, Columbus, Ohio.
Cancer Immunol Res. 2018 Dec;6(12):1499-1510. doi: 10.1158/2326-6066.CIR-18-0014. Epub 2018 Oct 23.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas resistant to most cancer treatments. Surgical resection remains the primary treatment, but this is often incomplete, ultimately resulting in high mortality and morbidity rates. There has been a resurgence of interest in oncolytic virotherapy because of encouraging preclinical and clinical trial results. Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells, lysing the cell and inducing antitumor immunity. We previously showed that basal interferon (IFN) signaling increases interferon-stimulated gene (ISG) expression, restricting viral replication in almost 50% of MPNSTs. The FDA-approved drug ruxolitinib (RUX) temporarily resets this constitutively active STAT signaling and renders the tumor cells susceptible to oHSV infection in cell culture. In the studies described here, we translated our results into a syngeneic MPNST tumor model. Consistent with our previous results, murine MPNSTs exhibit a similar IFN- and ISG-mediated oHSV-resistance mechanism, and virotherapy alone provides no antitumor benefit However, pretreatment of mice with ruxolitinib reduced ISG expression, making the tumors susceptible to oHSV infection. Ruxolitinib pretreatment improved viral replication and altered the oHSV-induced immune-mediated response. Our results showed that this combination therapy increased CD8 T-cell activation in the tumor microenvironment and that this population was indispensable for the antitumor benefit that follows from the combination of RUX and oHSV. These data suggest that JAK inhibition prior to oncolytic virus treatment augments both oHSV replication and the immunotherapeutic efficacy of oncolytic herpes virotherapy.
恶性外周神经鞘瘤（MPNST）是一种侵袭性软组织肉瘤，对大多数癌症治疗方法具有耐药性。手术切除仍然是主要治疗方法，但往往不彻底，最终导致高死亡率和发病率。由于令人鼓舞的临床前和临床试验结果，溶瘤病毒治疗再次受到关注。溶瘤单纯疱疹病毒（oHSV）选择性地在癌细胞中复制，裂解细胞并诱导抗肿瘤免疫。我们之前表明，基础干扰素（IFN）信号增加干扰素刺激基因（ISG）的表达，使近 50%的 MPNST 中的病毒复制受到限制。已批准用于临床的药物鲁索利替尼（RUX）暂时重置这种持续激活的 STAT 信号，使肿瘤细胞在细胞培养中易受 oHSV 感染。在本研究中，我们将研究结果转化为同源 MPNST 肿瘤模型。与我们之前的结果一致，小鼠 MPNST 表现出类似的 IFN 和 ISG 介导的 oHSV 耐药机制，单独的病毒疗法没有抗肿瘤益处。然而，鲁索利替尼预处理可降低 ISG 表达，使肿瘤易受 oHSV 感染。鲁索利替尼预处理可提高病毒复制并改变 oHSV 诱导的免疫介导反应。我们的结果表明，这种联合治疗可增加肿瘤微环境中 CD8 T 细胞的激活，而该群体对于 RUX 和 oHSV 联合治疗所带来的抗肿瘤益处是必不可少的。这些数据表明，在溶瘤病毒治疗之前进行 JAK 抑制可增强 oHSV 复制和溶瘤单纯疱疹病毒免疫治疗的疗效。
