Tumor-associated macrophages in vasogenic cerebral edema in brain tumors

脑肿瘤血管源性脑水肿中的肿瘤相关巨噬细胞

• 批准号: 10708165
• 负责人: Dolores Hambardzumyan
• 金额: $ 62万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708165
• 关键词: Ablation; Address; Adrenal Cortex Hormones; Anatomy; Antibodies; Antibody Therapy; Antineoplastic Agents; Area; Automobile Driving; Avastin; Binding; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cellular biology; Cerebral Edema; Chronic; Clinical; Complement; Complication; Data; Dexamethasone; Diabetes Mellitus; Diagnosis; Disease; Dose; Edema; Endothelial Cells; Exhibits; Frequencies; Genetic; Genetic Engineering; Genetically Engineered Mouse; Glioblastoma; Glioma; Human; Hypoxia; Immune response; Immunocompetent; Immunotherapy; Individual; Infiltration; Inflammatory; Interleukin-1 beta; Invaded; Link; Lymphoid; Macrophage; Malignant Neoplasms; Mediating; Mental Depression; Mesenchymal; Modality; Modeling; Molecular Biology; Molecular Target; Morbidity - disease rate; Mus; Myopathy; NF1 gene; Neoplasms; PDGFB gene; Pathology; Patients; Pericytes; Perioperative; Production; Prognosis; Proteins; Psychoses; Publishing; Radiation; Radiation therapy; Resistance development; Role; Severities; Signal Transduction; Steroids; Testing; Therapeutic; Tight Junctions; Time; Toxic effect; Treatment Efficacy; Tumor Cell Invasion; Tumor Promotion; Tumor-associated macrophages; VEGFA gene; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasogenic Cerebral Edema; Work; anti-cancer; anti-tumor immune response; cell type; cellular targeting; efficacy evaluation; epidermal growth factor receptor VIII; exhaust; human disease; in vivo; insight; monocyte; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; patient derived xenograft model; pharmacologic; public health relevance; side effect; targeted agent; therapy resistant; tool; traditional therapy; tumor; tumor growth; tumor microenvironment; vasogenic edema

Project Summary: Glioblastomas (GBM) are among the most lethal of all human cancers, with a median survival of around one year. Vasogenic edema is a universal problem for GBM patients, and corticosteroids are commonly used perioperatively to control cerebral edema and are frequently continued throughout subsequent treatment, notably radiotherapy (RT), for the amelioration of side effects. Vasogenic edema is a significant cause of morbidity in patients with both primary and metastatic brain tumors, both from the direct impact of edema and from indirect effects related to the requirement for chronic corticosteroid use to manage it. In general, the mechanism of edema formation is still unclear. We have shown that dexamethasone (DEX) administration significantly compromises RT efficacy, together with emerging new therapies that augment the immune response to treat brain tumors. Although we and others have identified antibodies and agents targeting vascular endothelial growth factor (VEGF) at high anti-cancer doses that effectively reduce edema, their use is associated with increased infiltration of tumor growth-promoting macrophages and development of resistance. Our preliminary and published work identified the pro-inflammatory IL-1β from blood-born monocyte/monocyte-derived macrophages (MDM) as a downstream target of DEX in exerting its anti-edema effect. We have shown that targeting IL-1β is as sufficient as DEX in reducing edema but does not compromise RT efficacy. In contrast to anti-VEGFA antibody treatment, targeting IL-1β does not induce increased infiltration of tumor-promoting TAMs; on the contrary, it decreases the number of tumor-promoting TAMs and reduces the number of exhausted CD8+ T-cells. This application thus aims to use three distinct genetically engineered mouse models of GBM that exhibit significant differences in TAMs and anatomical structures of the brain-blood barrier (BBB), together with human primary GBM patient-derived xenograft models, in combination with cell type specific IL-1β ablation strategies to determine detailed mechanisms of IL-1β effects on vascular permeability and edema formation in GBM. The proposed studies will provide new mechanistic insights into the fundamental cellular and molecular biology of IL- 1β in glioblastoma. The proposed studies test whether targeting IL-1β is a promising novel anti-edema therapy for heterogeneous GBM with dual efficacy –against edema (in our renewal application) and neoplastic growth that we demonstrated in our ongoing R01.

项目概要： 胶质母细胞瘤 (GBM) 是所有人类癌症中最致命的一种，中位生存期约为 1 年。血管源性水肿是GBM患者普遍存在的问题，常用皮质类固醇 围手术期控制脑水肿，并经常在后续治疗中持续进行，特别是 放射治疗（RT），用于改善副作用。血管源性水肿是发病的重要原因 患有原发性和转移性脑肿瘤的患者，无论是由于水肿的直接影响还是间接影响 与需要长期使用皮质类固醇来控制相关的影响。一般来说，其机制 水肿的形成仍不清楚。我们已经表明，地塞米松 (DEX) 给药显着 损害放疗疗效，以及增强免疫反应的新兴疗法 脑肿瘤。尽管我们和其他人已经确定了针对血管内皮生长的抗体和药物 高抗癌剂量的因子（VEGF）可以有效减少水肿，它们的使用与增加 促进肿瘤生长的巨噬细胞的浸润和耐药性的发展。我们的初步和 已发表的工作从血源性单核细胞/单核细胞衍生的巨噬细胞中鉴定出促炎性 IL-1β (MDM)作为DEX的下游靶点发挥其抗水肿作用。我们已经证明，靶向 IL-1β 是 与 DEX 一样足以减轻水肿，但不会影响 RT 疗效。与抗 VEGFA 抗体相比 治疗时，靶向 IL-1β 不会诱导促肿瘤 TAM 的浸润增加；相反，它 减少促肿瘤 TAM 的数量并减少耗尽的 CD8+ T 细胞的数量。这 因此，该申请旨在使用三种不同的 GBM 基因工程小鼠模型，这些模型表现出显着的 TAM 和脑血屏障 (BBB) 解剖结构的差异，以及人类初级 GBM 患者来源的异种移植模型，结合细胞类型特异性 IL-1β 消融策略， 确定 IL-1β 对 GBM 血管通透性和水肿形成影响的详细机制。这 拟议的研究将为 IL- 的基本细胞和分子生物学提供新的机制见解 胶质母细胞瘤中的 1β。拟议的研究测试靶向 IL-1β 是否是一种有前途的新型抗水肿疗法 针对具有双重功效的异质性 GBM——对抗水肿（在我们的更新应用中）和肿瘤生长 我们在正在进行的 R01 中展示了这一点。

项目成果

Immune Microenvironment in Glioblastoma Subtypes.

• DOI: 10.3389/fimmu.2018.01004
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Chen Z;Hambardzumyan D
• 通讯作者: Hambardzumyan D

Monocyte-neutrophil entanglement in glioblastoma.

• DOI: 10.1172/jci163451
• 发表时间: 2023-01-03
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Friedmann-Morvinski, Dinorah;Hambardzumyan, Dolores
• 通讯作者: Hambardzumyan, Dolores

Macrophages and microglia: the cerberus of glioblastoma.

• DOI: 10.1186/s40478-021-01156-z
• 发表时间: 2021-03-25
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Buonfiglioli A;Hambardzumyan D
• 通讯作者: Hambardzumyan D

Tumour immune landscape of paediatric high-grade gliomas.

儿童高级别胶质瘤的肿瘤免疫景观。

• DOI: 10.1093/brain/awab155
• 发表时间: 2021
• 期刊: Brain : a journal of neurology
• 作者: Ross,JamesL;VelazquezVega,Jose;Plant,Ashley;MacDonald,TobeyJ;Becher,OrenJ;Hambardzumyan,Dolores
• 通讯作者: Hambardzumyan,Dolores