Leveraging Zika virus driven myeloid cell responses to treat GBM

利用寨卡病毒驱动的骨髓细胞反应来治疗 GBM

• 批准号: 10891973
• 负责人: Jason A. Chesney
• 金额: $ 14.82万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10891973
• 关键词: Address; Antigen Presentation; Automobile Driving; CD8-Positive T-Lymphocytes; Cancer Center; Combined Modality Therapy; Dendritic Cells; Environment; FLT3 ligand; Failure; Glioblastoma; Goals; Immune; Immunotherapy; Inflammatory; Maps; Myeloid Cells; Oncolytic viruses; Research; Role; Solid Neoplasm; T cell response; Therapeutic; Tropism; Zika Virus; antitumor effect; cancer immunotherapy; draining lymph node; monocyte; novel; oncolytic virotherapy; programs; response; stem cells; tumor; tumor immunology; tumor microenvironment

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.

溶瘤病毒治疗对高级别实体瘤有希望，但没有一种显示出治疗潜力。本研究探索了利用寨卡病毒（ZIKV）的天然趋向性靶向胶质母细胞瘤干细胞（GSCs）的潜力，并将典型的免疫抑制GBM肿瘤环境重编程为诱导GBM特异性CD8+ T细胞反应的炎症、抗原呈递环境。本提案的第一个目标是确定在寨卡病毒治疗后驱动抗肿瘤T细胞反应的细胞机制。我们的研究将研究ZIKV治疗后诱导的两种不同的髓细胞亚群-肿瘤微环境（TME）中的CCR2+单核细胞和引流淋巴结（dLN）中的树突状细胞亚群-2 (DC-2s) -在驱动抗肿瘤T细胞对GBM的反应中的功能作用。此外，我们的研究将检验一种高度新颖的Flt3配体疗法和ZIKV联合疗法的协同治疗潜力，作为激活树突状细胞亚群1 （dc -1）和DC-2的策略，以最大限度地提高抗肿瘤CD8+ T细胞反应和随后的GBM排斥反应。这项研究具有重要意义，因为1)它解决了ZIKV作为GBM治疗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。