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.

溶瘤病毒疗法显示出对高级实体瘤的有希望，但没有证明可以提供治疗潜力。这项研究探讨了利用寨卡病毒（ZIKV）的自然向潮流的潜力，以靶向胶质母细胞瘤干细胞（GSC），并重新编程典型的免疫抑制GBM肿瘤环境，以诱导GBM特定的CD8+ T细胞反应，以诱导炎症，抗原呈现的环境。该提案的第一个目标是确定ZIKV处理后驱动抗肿瘤T细胞反应的细胞机制。我们的研究将研究ZIKV治疗后引起的两个不同的髓样细胞子集的功能作用-CCR2+单核细胞在肿瘤微环境（TME）和树突状细胞子集和树突状细胞子集（DC-2）中，在排水淋巴结（DLN）中 - 在驱动抗肿瘤T细胞抗肿瘤T细胞反应中。此外，我们的研究将研究高度新颖的FLT3配体治疗和ZIKV组合疗法的协同治疗潜力，作为激活树突状细胞子集（DC-1）和DC-2的策略，以最大程度地提高抗肿瘤CD8+ T细胞反应以及随后的GBM抑制。这项研究很重要，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）解决了免疫疗法的当前失败，并将治疗路径映射出来。