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Immune-suppressive Myeloid Cells in the Glioma Microenvironment: Signaling Mechanisms and Novel Therapeutic Strategies

胶质瘤微环境中的免疫抑制骨髓细胞：信号传导机制和新的治疗策略

基本信息

批准号：
9304356
负责人：
Maria G Castro
金额：
$ 40.37万
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：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304356
关键词：
Ablation Address Adhesions Adjuvant Adjuvant Therapy Adult Animals Antibodies Antigens Blood - brain barrier anatomy Blood Circulation Bone Marrow CXCL12 gene CXCR4 gene Cells Cessation of life Clinical Cytotoxic T-Lymphocyte-Associated Protein 4 DNA Microarray Chip Data Diagnosis Dioxygenases Disease Progression Effector Cell FLT3LG gene Failure Genetic Genetic Engineering Genetically Engineered Mouse Glioblastoma Glioma Heterogeneity Human ITGAM gene Immune Immune response Immunosuppression Immunosuppressive Agents Immunotherapy Impairment In Situ In Vitro Infiltration Interleukin-10 Intracranial Neoplasms Leucocytic infiltrate Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Microarray Analysis Modeling Molecular Mus Mutation Myelogenous Myeloid Cells Operative Surgical Procedures PDCD1LG1 gene Patients Peripheral Permeability Pharmacology Phase Play Primary Brain Neoplasms Progression-Free Survivals Proliferating Radiation Radiation therapy Recruitment Activity Regulatory T-Lymphocyte Role Signal Transduction Sleeping Beauty Suppressor-Effector T-Lymphocytes T cell response T-Lymphocyte Testing Therapeutic Transforming Growth Factor beta Translating Tumor Cell Invasion Tumor Immunity Tumor-Associated Vasculature Tumorigenicity cell type chemotherapy cytokine cytotoxic experimental study gene therapy genetic makeup immunocytochemistry improved in vivo in vivo Model macrophage migration monocyte mouse model neoplastic cell new therapeutic target novel novel therapeutics public health relevance receptor therapy resistant tumor tumor microenvironment tumor progression tumorigenic vaccine trial

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults; median survival from diagnosis is ~15-21 months. Anti-GBM immune strategies constitute novel and exciting therapeutic adjuvants to improve survival due to surgery, chemo- and radiotherapy. However, it has been challenging to develop effective anti-GBM immune responses that translate into increased patients' survival. As systemic immune responses against GBM antigens can be induced, clinical failure is thought to be due to powerful GBM induced immune suppression. Immune suppression in GBM patients is mediated by various mechanisms that include immature myeloid cells (IMCs) that accumulate in the tumor microenvironment. Subtypes of immature myeloid cells are: (i) myeloid derived suppressor cells (MDSCs), (ii) immunosuppressive tumor associated macrophages (TAMs), and, (iii) Tie2+ monocytes (TEMs). GBMs recruit immature myeloid cells to the tumor microenvironment where they inhibit anti-tumor immune responses, for example, by directly inhibiting T-cell effector function. Additional immune suppressive mechanisms involve: accumulation of Tregs, immunosuppressive molecules (i.e., indoleamine2, 3-dioxygenase 1 (IDO), cytotoxic T-lymphocyte antigen 4 (CTLA4), and programmed death 1 receptor ligand (PDL1), and cytokines, (i.e., IL10, TGFβ). To identify secreted factors which attract immune-suppressive IMCs into the GBM microenvironment we performed DNA microarray analysis on endogenous and transplantable mouse and human GBM cells and identified CXCL12 as a possible candidate. We also identified CXCR4, the cognate CXCL12 receptor, on immature myeloid cells within the GBM microenvironment supporting the hypothesis that CXCL12/CXCR4 plays an important role in attracting IMCs to the GBM microenvironment. To ascertain the role played by CXCL12-CXCR4 signaling in GBM progression and in regulating anti-GBM immune therapies, we propose to use an immune competent, genetically engineered endogenous mouse GBM model. Intracranial tumors are induced by Sleeping Beauty (SB)-mediated insertion of genetic alterations found in human GBM. Preliminary data show that conditioned media from both transplantable and SB-induced GBM elicit a high level of IMCs' expansion in vitro. In GBM models in vivo, we observed accumulation of IMCs within the GBM microenvironment and in the peripheral circulation. CXCR4 blockade significantly prolonged median survival of mice bearing endogenous GBM. We will use CXCL12 and/or CXCR4 gene ablation models to test the hypothesis that CXCL12-CXCR4 signaling axis plays a major role in determining the immune profile, both qualitatively and quantitatively, of the GBM microenvironment and thus has profound effects on disease progression. We further hypothesize that blocking accumulation of IMCs in combination with anti-GBM immune stimulatory strategies will provide a powerful adjuvant approach to treat malignant brain cancer.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑肿瘤；诊断后的中位生存期约为 15-21 个月。抗 GBM 免疫策略构成了新颖且令人兴奋的治疗佐剂，可提高手术、化疗和放疗的生存率。然而，开发有效的抗 GBM 免疫反应以提高患者的生存率一直是一项挑战。由于可以诱导针对 GBM 抗原的全身免疫反应，因此临床失败被认为是由于 GBM 诱导的强大免疫抑制所致。 GBM 患者的免疫抑制是由多种机制介导的，其中包括在肿瘤微环境中积累的未成熟骨髓细胞 (IMC)。未成熟骨髓细胞的亚型是：(i) 骨髓源性抑制细胞 (MDSC)、(ii) 免疫抑制性肿瘤相关巨噬细胞 (TAM) 和 (iii) Tie2+ 单核细胞 (TEM)。 GBM 将未成熟的骨髓细胞招募到肿瘤微环境中，在其中抑制抗肿瘤免疫反应，例如，通过直接抑制 T 细胞效应器功能。其他免疫抑制机制包括：Tregs、免疫抑制分子（即吲哚胺2、3-双加氧酶 1 (IDO)、细胞毒性 T 淋巴细胞抗原 4 (CTLA4) 和程序性死亡 1 受体配体 (PDL1) 和细胞因子（即 IL10、TGFβ）的积累。我们对内源性和可移植的小鼠和人 GBM 细胞进行 DNA 微阵列分析，并确定 CXCL12 作为可能的候选者。我们还在 GBM 微环境中的未成熟骨髓细胞上发现了 CXCR4（同源 CXCL12 受体），支持以下假设： CXCL12/CXCR4 在吸引 IMC 进入 GBM 微环境方面发挥着重要作用。为了确定 CXCL12-CXCR4 信号在 GBM 进展和调节抗 GBM 免疫治疗中的作用，我们建议使用具有免疫能力的基因工程内源性小鼠 GBM 模型。颅内肿瘤是由睡美人（SB）介导诱发的插入在人类 GBM 中发现的基因改变。初步数据显示，来自可移植 GBM 和 SB 诱导 GBM 的条件培养基均可在体外引起高水平的 IMC 扩增。在体内 GBM 模型中，我们观察到 IMC 在 GBM 微环境和外周循环中的积累。 CXCR4阻断显着延长了小鼠的中位生存期内源性GBM。我们将使用 CXCL12 和/或 CXCR4 基因消融模型来检验以下假设：CXCL12-CXCR4 信号轴在定性和定量确定 GBM 微环境的免疫特征方面发挥重要作用，从而对疾病进展产生深远影响。我们进一步假设，结合抗 GBM 免疫阻断 IMC 的积累刺激策略将为治疗恶性脑癌提供强大的辅助方法。