Tumor-associated macrophages in vasogenic cerebral edema in brain tumors

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.