Leveraging Zika virus driven myeloid cell responses to treat GBM

溶瘤病毒治疗显示出对高级别实体瘤的希望，但没有一种显示出提供治愈潜力。这项研究探索了利用寨卡病毒（ZIKV）的天然嗜性靶向胶质母细胞瘤干细胞（GSC）并将通常的免疫抑制性GBM肿瘤环境重新编程为诱导GBM特异性CD 8 + T细胞反应的炎症抗原呈递环境的潜力。该提案的第一个目标是确定ZIKV治疗后驱动抗肿瘤T细胞应答的细胞机制。我们的研究将检查ZIKV治疗后诱导的两种不同的骨髓细胞亚群-肿瘤微环境（TME）中的CCR 2+单核细胞和引流淋巴结（dLN）中的树突状细胞亚群-2（DC-2s）-在驱动针对GBM的抗肿瘤T细胞应答中的功能作用。此外，我们的研究将检查高度新颖的Flt 3配体疗法和ZIKV组合疗法作为激活树突状细胞亚群-1（DC-1 s）和DC-2的策略的协同治疗潜力，以最大化抗肿瘤CD 8 + T细胞应答和随后的GBM排斥。这项研究意义重大，因为1）它解决了ZIKV作为GBM治疗的有效溶瘤病毒的潜力，2）确定了有助于其抗肿瘤作用的关键细胞机制，3）解决了目前免疫治疗的失败并绘制了治疗路径。

Oncolytic viral therapy shows promise for high-grade solid tumors, but none have been shown to provide curative potential. This study explores the potential of harnessing the natural tropism of Zika virus (ZIKV) to target glioblastoma stem cells (GSCs) and reprogram the typically immune suppressive GBM tumor environment to an inflammatory, antigen-presenting environment that induces GBM-specific CD8+ T cell responses. The first goal of this proposal is to identify the cellular mechanisms that drive anti-tumor T cell responses following ZIKV treatment. Our research will examine the functional roles of two distinct myeloid cell subsets induced following ZIKV treatment - CCR2+ monocytes in the tumor microenvironment (TME) and dendritic cell subset-2 (DC-2s) in draining lymph nodes (dLN) - in driving anti-tumor T cell responses against GBM. Additionally, our study will examine the synergistic therapeutic potential of a highly novel Flt3 ligand therapy and ZIKV combination therapy as a strategy to activate both dendritic cell subset-1 (DC-1s) and DC-2, to maximize anti-tumor CD8+ T cell responses and subsequent GBM rejection. This research is significant because 1) it addresses the potential of ZIKV as an effective oncolytic virus for GBM treatment, 2) identifies key cellular mechanisms that contribute to its anti-tumor effects and 3) addresses the current failure of immunotherapy and maps a therapeutic path forward.