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：
9981837
负责人：
Maria G Castro
金额：
$ 44.36万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981837
关键词：
Ablation Address Adhesions Adjuvant Adjuvant Therapy Adult Animals Antibodies Antigens Blood - brain barrier anatomy Blood Circulation Bone Marrow CTLA4 gene CXCL12 gene CXCR4 gene Cells Chemotherapy and/or radiation Clinical DNA Microarray Chip Data Diagnosis Dioxygenases Disease Progression Endothelium FLT3 ligand Failure Genetic Genetic Engineering Genetically Engineered Mouse Glioblastoma Glioma Heterogeneity Human ITGAM gene Immune Immune response Immunocompetent Immunosuppression 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 Myeloid-derived suppressor cells Operative Surgical Procedures Patients Peripheral Permeability Pharmacology Phase Play Primary Brain Neoplasms Progression-Free Survivals Proliferating Radiation therapy Regulatory T-Lymphocyte Role Signal Transduction Sleeping Beauty T cell response T-Lymphocyte Testing Therapeutic Transforming Growth Factor beta Translating Transplantation Tumor Cell Invasion Tumor Immunity Tumor-Associated Vasculature Tumor-associated macrophages Tumor-infiltrating immune cells anti-tumor immune response antigen-specific T cells cell type cytokine cytotoxic effector T cell experimental study gene therapy genetic makeup immunocytochemistry improved in vivo in vivo Model migration monocyte mouse model neoplastic cell new therapeutic target novel novel therapeutics programmed cell death ligand 1 programmed cell death protein 1 public health relevance receptor recruit 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（由适用提供）：多形胶质母细胞瘤（GBM）是成年人最常见的原发性恶性脑肿瘤；诊断的中位生存期为〜15-21个月。抗GBM免疫策略构成了新颖和令人兴奋的治疗调节剂，以提高由于手术，化学和放射疗法而引起的生存。但是，开发有效的抗GBM免疫反应的挑战是转化为患者生存率增加的。由于可以诱导针对GBM抗原的全身免疫反应，因此临床衰竭被认为是由于强大的GBM诱导的免疫抑制作用所致。 GBM患者的免疫抑制是由包括未成熟的髓样细胞（IMC）在肿瘤微环境中积累的各种机制介导的。未成熟的髓样细胞的亚型为：（i）髓样衍生的抑制细胞（MDSC），（ii）免疫抑制性肿瘤相关的巨噬细胞（TAMS），以及（III）TIE2+单核细胞（TEMS）。 GBMS将未成熟的髓样细胞募集到肿瘤微环境中，它们可以通过直接抑制T细胞效应子功能来抑制抗肿瘤免疫复杂。其他免疫抑制机制涉及：Treg，免疫抑制分子的积累（即吲哚胺2，3-二氧酶1（IDO），细胞毒性T-淋巴细胞抗原4（CTLA4）和programmed Death 1和ProgramMed Medismed Death 1，以及ProgramMed Medicmed Death 1受体3（PDL1）和Cytokiness和Cytokiness，In。分泌的因素将免疫抑制的IMC吸引到GBM微环境中，我们对内源性和可移植小鼠和人类GBM细胞进行了DNA微阵列分析，并确定了CXCL1的CXCR4，我们还识别出Cognate CXCL12受体的cxcl12受体。 CXCL12/cxcr4在吸引IMC到GBM微环境中起着重要作用，以确定CXCL12-CXCR4信号在GBM进展中的作用，并在调节抗GBM免疫疗法中，我们建议使用免疫胜任的，基因工程的内生鼠标。在人类GBM中发现的遗传改变的插入。初步数据表明，从可移植和SB诱导的GBM中调节培养基会引起高水平的IMC在体外扩张。在体内GBM模型中，我们观察到IMC在GBM微环境中和周围循环中的积累。 CXCR4阻滞显着延长了内源性GBM的小鼠的培养基存活。我们将使用CXCL12和/或CXCR4基因消融模型来检验以下假设：CXCL12-CXCR4信号轴在确定GBM微环境的定性和定量上，在确定免疫特征方面起着重要作用，从而对疾病进展产生了深远影响。我们进一步假设，与抗GBM免疫刺激策略结合结合IMC的积累将提供强大的可调节方法来治疗恶性脑癌。