Neuroimmunology of Malignant Brain Tumors: Innate Mechanisms

 描述（由申请人提供）：对胶质瘤（GBM）的先天免疫应答知之甚少。大多数研究都集中在适应性T细胞免疫反应。先天免疫应答被认为主要是激活T细胞应答所需，而不是介导针对肿瘤的直接细胞毒性。最近，我们发现NK细胞抑制GBM进展，并发挥强大的抗GBM细胞毒性。反过来，为了逃避NK杀伤，GBM产生了NK细胞的有效抑制剂。在确定NK细胞抑制GBM生长和侵袭后，我们将评估先天免疫细胞的复杂网络和负责这种强大的抗GBM反应的信号通路。我们的数据支持这样的假设，即除了NK细胞之外，其他先天性免疫细胞对于强大的NK介导的抗GBM应答是必需的，因为GR 1耗竭消除了NK介导的GBM杀伤。在AIM 1中，将鉴定抑制GBM进展所需的先天免疫细胞网络。我们的初步数据表明，Myd 88信号传导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需的。在AIM 2中，我们将测试Myd 88在肿瘤微环境内的髓系细胞中转导对TLR 9、IL 18和/或IL 33信号传导的细胞应答的假设。我们将评估NK细胞杀死GBM细胞需要哪些细胞Myd 88信号传导。初步数据表明，cGAS-STING-IFNβ途径也是NK介导的GBM杀伤所必需的。在AIM 3中，我们将检验以下假设：通过pDC或其他骨髓细胞上的cGAS-STING-IRF 3-IFNβ途径的信号传导对于完全细胞毒性NK活化是必要的。我们建议测试这两种途径（Myd 88和STING）是否是先天免疫介导的GBM进展抑制所必需的。总之，我们的建议将确定先天免疫细胞和信号通路的网络，共同抑制GBM的进展。此外，所提出的工作还将确定两种先天信号传导途径（Myd 88和STING）是否会聚以刺激恶性GBM杀伤。复杂的先天免疫网络及其通过Myd 88和STING的信号传导仅通过先天免疫抑制脑肿瘤进展尚未阐明。最后，我们将在GBM的基因工程小鼠模型中测试条件性细胞毒性免疫刺激方法（Ad-TK Ad-Flt 3L）与先天免疫信号传导途径（Myd 88和STING）的激活的治疗组合。从长远来看，我们的目标是开发新的翻译临床试验，因为我们已经实现了早期使用Ad-TK和Ad-Flt 3L（NCT 01811992）的基因/免疫治疗人类胶质瘤。

 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).