Neuroimmunology of Malignant Brain Tumors: Innate Mechanisms

恶性脑肿瘤的神经免疫学：先天机制

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：对神经胶质瘤（GBM）的先天免疫复杂率很少。大多数研究都集中在适应性T细胞免疫回报上。认为先天免疫调查是必需的，以激活T细胞反应，而不是介导针对肿瘤的直接细胞毒性。最近，我们表明NK细胞抑制GBM进展，并发挥强大的抗GBM细胞毒性。反过来，逃避NK杀死GBM会产生潜在的NK细胞抑制剂。确定NK细胞抑制了GBM的生长和侵袭，我们将评估固有免疫细胞的复杂网络以及负责这种强大的抗GBM反应的信号通路。我们的数据支持以下假设：除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部署废除了NK介导的GBM杀戮。在AIM 1中，将确定抑制GBM进展所需的先天免疫细胞网络。我们的初步数据表明，MyD88信号对于将先天免疫细胞运输到肿瘤微环境并控制肿瘤生长是必要的。在AIM 2中，我们将测试MyD88的假设，即MyD88翻译了对TLR9，IL18和/或IL33信号在肿瘤微环境内的细胞中的细胞反应。我们将评估NK细胞杀死GBM细胞需要哪些细胞MyD88信号传导。初步数据表明，对于NK介导的GBM杀戮，CGAS-Sting-IFNβ途径也是必需的。在AIM 3中，我们将测试以下假设：PDCS-或其他髓样细胞在PDCS上通过CGAS-STING-IRF3-IFNβ途径进行信号是全细胞毒性NK激活所必需的。我们建议测试对先天免疫介导的GBM进展抑制是否必要的途径（MyD88和STING）。总而言之，我们的建议将确定共同抑制GBM进展的先天免疫电池细胞和信号通路的网络。此外，提出的工作还将确定两个先天信号通路（MyD88和STING）是否汇聚以刺激恶性GBM杀戮。复杂的先天免疫电池网络及其通过MyD88的信号传导，并仅通过先天免疫组织化学抑制脑肿瘤进展，尚未阐明。最后，我们将测试有条件的细胞毒性免疫刺激方法（AD-TK AD-FLT3L）的治疗组合，并在一般工程的GBM小鼠模型中激活先天免疫信号通路（MyD88和STING）。从长远来看，我们旨在开发新型翻译的临床试验，就像我们先前使用AD-TK和AD-FLT3L（NCT01811992）对人神经胶质瘤进行基因/免疫治疗治疗的基因/免疫治疗。