Tumor-associated macrophages in vasogenic cerebral edema in brain tumors

项目总结： 胶质母细胞瘤(GBM)是所有人类癌症中最致命的，平均存活率约为1 年。血管源性水肿是GBM患者的普遍问题，皮质类固醇是常用的治疗方法。 围手术期控制脑水肿，并经常持续到随后的治疗，值得注意的是 放射治疗(RT)，用于改善副作用。血管源性浮肿是发病的重要原因 同时患有原发和转移性脑肿瘤的患者，既有直接的影响，也有间接的影响 与长期使用皮质类固醇来管理它的要求有关的影响。总的来说，这一机制 水肿的形成仍不清楚。我们已经证明地塞米松(DEX)的使用显著 折衷RT疗效，以及不断涌现的增强免疫反应的新疗法 脑瘤。尽管我们和其他人已经确定了针对血管内皮细胞生长的抗体和试剂 高剂量抗癌因子(血管内皮生长因子)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侵袭和抗药性的发展。我们的初选和 已发表的研究从血源性单核细胞/单核细胞来源的巨噬细胞中鉴定出促炎症的IL-1β 地塞米松(MDM)作为地塞米松的下游靶点发挥其抗水肿作用。我们已经证明，靶向IL-1β是 在减轻水肿方面与地塞米松一样充足，但不影响RT的疗效。与抗VEGFA抗体相反 靶向IL-1β的治疗并不会导致促肿瘤TAM的渗透增加；相反，它 减少促进肿瘤的TAM的数量，减少耗尽的CD8 T细胞的数量。这 因此，应用程序的目标是使用三种不同的GBM基因工程小鼠模型，这些模型显示出显著的 脑-血屏障(BBB)的TAM和解剖结构与人类原发疾病的差异 基底膜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影响基底膜血管通透性和水肿形成的详细机制。这个 拟议的研究将为IL-2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1例β。拟议中的研究测试了靶向IL-1β是否是一种有前途的新型抗水肿疗法 对于具有双重功效的异种GBM-抗水肿(在我们的续订应用中)和肿瘤生长 我们在正在进行的R01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.