Tumor-associated macrophages in vasogenic cerebral edema in brain tumors

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，中位存活率约为1 年血管源性水肿是GBM患者的普遍问题，通常使用皮质类固醇 围手术期控制脑水肿，并经常在随后的治疗中继续， 放疗（RT），以改善副作用。血管源性水肿是一个重要的原因发病， 原发性和转移性脑肿瘤患者，无论是从水肿的直接影响， 与需要长期使用皮质类固醇来管理它有关的影响。一般来说， 水肿形成仍不清楚。我们已经证明，地塞米松（DEX）的管理显着 损害RT疗效，以及新兴的新疗法，增强免疫反应， 脑瘤虽然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 在高抗癌剂量下，有效减少水肿的VEGF因子，其使用与增加 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 已发表的工作从血生单核细胞/单核细胞衍生的巨噬细胞中鉴定出促炎性IL-1β (MDM)作为DEX发挥其抗水肿作用的下游靶点。我们已经证明，靶向IL-1β是 在减轻水肿方面与DEX一样充分，但不影响RT疗效。与抗VEGFA抗体相比， 治疗中，靶向IL-1β不会诱导肿瘤促进TAM的浸润增加;相反， 减少肿瘤促进TAM的数量，并减少耗尽的CD 8 + T细胞的数量。这 因此，本申请旨在使用三种不同的GBM基因工程小鼠模型， 脑血屏障（BBB）的TAM和解剖结构的差异，以及人类原发性 GBM患者来源的异种移植物模型，与细胞类型特异性IL-1β消融策略组合， 确定IL-1β对GBM中血管通透性和水肿形成的作用的详细机制。的 提出的研究将提供新的机制见解的基本细胞和分子生物学的IL- 1β在胶质母细胞瘤中。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 对于异质性GBM具有双重功效-抗水肿（在我们的更新申请中）和肿瘤生长 我们正在进行的R 01中展示了这一点。

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.