Neuroimmunology of Malignant Brain Tumors: Innate Mechanisms

恶性脑肿瘤的神经免疫学：先天机制

• 批准号: 9115388
• 负责人: Pedro R Lowenstein
• 金额: $ 40.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115388
• 关键词: Ablation; Agonist; Antibodies; Brain Neoplasms; Cell Line; Cells; Complement; Complex; DNA; Data; Dendritic Cells; Development; Dinucleoside Phosphates; Fluorescence; Galectin 1; Genes; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Human; IL18 gene; IRF3 gene; ITGAM gene; Image; Immune; Immune response; Immune system; Immunity; Immunotherapy; Individual; Infectious Agent; Infiltration; Inflammatory; Interferon-alpha; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; MicroRNAs; Microscopy; Modeling; Molecular; Monitor; Mus; Myeloid Cells; Natural Immunity; Natural Killer Cells; Neoplasms; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Process; Production; Recruitment Activity; Resistance; Rodent; Signal Pathway; Signal Transduction; T cell response; T-Lymphocyte; TLR7 gene; TNF gene; Testing; Therapeutic; Time; Transgenic Mice; Tumor-Derived; Work; adaptive immunity; brain parenchyma; cell type; chemokine; cytokine; cytotoxic; cytotoxicity; ds-DNA; immune clearance; implantation; improved; in vivo; inhibitor/antagonist; killings; monocyte; mouse model; neuroimmunology; novel; overexpression; public health relevance; response; trafficking; translational clinical trial; tumor; tumor DNA; tumor eradication; tumor growth; tumor microenvironment; tumor progression; two-photon

 DESCRIPTION (provided by applicant): Innate immune responses against glioma (GBM) are poorly understood. Most studies have focused on adaptive T cell immune responses. Innate immune responses are thought to be needed primarily, to activate T cell responses, rather than mediate direct cytotoxicity against tumors. Recently we showed that NK cells inhibit GBM progression, and exert powerful anti- GBM cytotoxicity. In turn, to evade NK- killing GBMs produce potent inhibitors of NK cells. Having established that NK cells inhibit GBM growth and invasion, we will evaluate the complex network of innate immune cells and signaling pathways responsible for this powerful anti-GBM response. Our data support the hypothesis that other innate immune cells, besides NK cells, are necessary for the powerful NK-mediated anti-GBM responses, as GR1 depletion abolishes NK- mediated GBM killing. In AIM 1 will identify the network of innate immune cells required to inhibit GBM progression. Our preliminary data show that Myd88 signaling is necessary for trafficking of innate immune cells to the tumor microenvironment and control tumor growth. In AIM 2 we will test the hypothesis that Myd88 transduces cellular responses to TLR9, IL18, and/or IL33 signaling in cells of the myeloid lineage within the tumor microenvironment. We will assess in which cells Myd88 signaling is needed for NK cells to kill GBM cells. Preliminary data suggest that the cGAS-STING-IFNβ pathway is also necessary for NK-mediated GBM killing. In AIM 3 we will test the hypothesis that signaling via the cGAS-STING-IRF3-IFNβ pathway on pDCs -or other myeloid cells- is necessary for full cytotoxic NK activation. We propose to test whether both pathways (Myd88 and STING) are necessary for innate immune-mediated inhibition of GBM progression. In summary, our proposal will ascertain the network of innate immune cells and signaling pathways that jointly inhibit GBM progression. In addition, the work proposed will also establish if the two innate signaling pathways (Myd88 and STING) converge to stimulate malignant GBM killing. The complex innate immune network and its signaling through Myd88 and STING to inhibit brain tumor progression solely via innate immunity have not yet been elucidated. Finally, we will test therapeutic combinations of a conditional cytotoxic-immune stimulatory approach (Ad-TK Ad-Flt3L) with the activation of innate immune signaling pathways (Myd88 and STING) in genetically engineered mouse models of GBM. In the long term, we aim to develop novel translational clinical trials, as we achieved earlier for gene/immune-therapeutic treatment of human gliomas using Ad-TK and Ad-Flt3L (NCT01811992).

 描述(由申请人提供)：对胶质瘤的先天免疫反应(GBM)知之甚少。大多数研究都集中在适应性T细胞免疫反应上。先天免疫反应被认为主要是为了激活T细胞反应，而不是介导对肿瘤的直接细胞毒性。最近我们发现NK细胞可以抑制GBM的进展，并发挥强大的抗GBM细胞毒作用。反过来，为了逃避NK杀伤，GBM会产生有效的NK细胞抑制物。在确定NK细胞抑制GBM的生长和侵袭后，我们将评估由天然免疫细胞和信号通路组成的复杂网络，这些信号通路负责这种强大的抗GBM反应。我们的数据支持这一假设，即除了NK细胞外，其他先天免疫细胞对于强大的NK介导的抗GBM反应是必需的，因为GR1缺失取消了NK介导的GBM杀伤。在AIM中，1将确定抑制GBM进展所需的先天免疫细胞网络。我们的初步数据显示，MyD88信号是先天免疫细胞运输到肿瘤微环境和控制肿瘤生长所必需的。在AIM 2中，我们将测试假设MyD88在肿瘤微环境中的髓系细胞中传递对TLR9、IL18和/或IL33信号的反应。我们将评估NK细胞在哪些细胞中需要MyD88信号来杀伤GBM细胞。初步数据表明，cGAS-STING-干扰素β通路也是NK介导的基底膜杀伤所必需的。在目标3中，我们将测试假设，即通过PDCs或其他髓系细胞上的cGAS-sting-irf3-干扰素β通路的信号是充分激活细胞毒性NK所必需的。我们建议测试这两条途径(MyD88和STING)是否对先天免疫介导的抑制GBM进展是必要的。总之，我们的建议将确定共同抑制GBM进展的先天免疫细胞和信号通路的网络。此外，这项拟议的工作还将确定这两条天生的信号通路(MyD88和STING)是否会聚在一起，刺激恶性的GBM杀伤。复杂的先天免疫网络及其通过MyD88和STING单独通过先天免疫抑制脑瘤进展的信号尚未阐明。最后，我们将测试条件性细胞毒免疫刺激方法(Ad-TK Ad-Flt3L)与激活天然免疫信号通路(MyD88和STING)的治疗组合在基因工程小鼠的GBM模型中。从长远来看，我们的目标是开发新的转化型临床试验，就像我们早先实现的使用Ad-TK和Ad-Flt3L治疗人脑胶质瘤的基因/免疫治疗一样(NCT01811992)。