The trusted source for
healthcare information and
By Evan Noch, MD, PhD
Instructor, Department of Neurology, Weill Cornell Medical College
Dr. Noch reports no financial relationships relevant to this field of study.
SYNOPSIS: Glioblastoma-associated cerebral edema is a dreaded aspect of these tumors. Accumulating evidence suggests that immune dysregulation by glioblastoma cells induces tumor-associated edema and that disruption of this tumor-immune interaction may represent a novel strategy to reduce cerebral edema in glioblastoma.
SOURCE: Herting CJ, Chen Z, Maximov V, et al. Tumour-associated macrophage-derived interleukin-1 mediates glioblastoma-associated cerebral oedema. Brain 2019;142:3834-3851.
Glioblastoma remains one of the most lethal human cancers, with five-year survival of just 5.6% despite surgical debulking, chemotherapy, and radiation. There have been only incremental improvements in overall survival for glioblastoma in the past 15 years, due largely to difficulties in blood-brain barrier penetration, intrinsic tumor heterogeneity, and bypass mechanisms that render single-target approaches ineffective. One area of glioblastoma that has gained more recent awareness is the neurological sequelae of this devastating disease, both as a result of underlying biology and because of treatment. Cerebral edema often is a presenting feature of glioblastoma but also is caused by a variety of cytotoxic treatments and results in significant morbidity. On a biological level, glioblastoma-associated cerebral edema can result from a variety of mechanisms, including glutamate excitotoxicity that kills surrounding neurons to increase space to grow, tumor-induced inflammation, and dysregulated vasculature resulting from tumor-induced blood vessel thrombosis.
Herting et al demonstrated a new glioblastoma-immune axis that regulates tumor-associated cerebral edema. For their glioblastoma mouse models, they used the well-established Ntv-a/Cyclin-dependent kinase 2a (Cdkn2a)-/-, platelet-derived growth factor B (PDGFB)-overexpressing glioblastoma model. Using an innovative technique of co-culturing bone marrow-derived macrophages (BMDMs) or microglia with organotypic tumor slices isolated from tumor-bearing mice, they show that BMDMs upregulate the interleukins, IL1a and IL1b, when cultured with the tumor slices. Interestingly, microglia exhibit the opposite response, with IL1a and IL1b downregulation. In this ex vivo model, dexamethasone treatment suppressed the BMDM response, leading to downregulation of both IL1a and IL1b, indicating that dexamethasone may impair the ability of glioblastoma cells to recruit BMDMs.
Through immune cell-profiling of excised tumors from mice, they found that dexamethasone-treated mice exhibited a reduction in tumor-associated myeloid cells and that this reduction was wholly explained by a reduction in the infiltration of BMDMs. Dexamethasone also impaired the ability of lymphoid cells to infiltrate the tumor. Notably, they did not find any effect of dexamethasone on markers of angiogenesis. Since they hypothesized that IL-1 signaling mediated the connection between glioblastoma and BMDM infiltration, they genetically ablated expression of IL-1 receptor (IL-1R) in their in vivo model. Indeed, immune cell profiling of these tumors demonstrated significant reduction in tumor-associated macrophages from Ntv-a/Il1r1-/- mice compared to tumors from Ntv-a mice. Adapting an assay that examines leakage of Hoechst dye through the blood-brain barrier, they also found that genetic ablation of IL-1R reduced blood-brain barrier permeability, similar to the clinical effects of dexamethasone or vascular endothelial growth factor (VEGF) blockade.
To identify the ligands that mediate the IL-1R effect, they examined the role of the interleukins, IL1a and IL1b, which both signal through IL-1R. For these studies, they used a previously established MRI-based assessment of tumor edema. They genetically ablated expression of these interleukins in their glioblastoma model and found that loss of IL1a alone or both IL1a and IL1b led to a dramatic reduction in tumor edema, establishing that glioblastoma cells signal through the IL-1 pathway to regulate tumor edema.
From a therapeutic perspective, dexamethasone has been demonstrated to impair radiation efficacy in glioblastoma through a variety of mechanisms, including regulation of immune infiltration and the blood-brain barrier. The authors sought to establish through genetic and pharmacological methods that IL-1 inhibition may be a suitable alternative to dexamethasone for the treatment of tumor-associated edema. Compared to Ntv-a mice, Ntv-a/Il1a/b-/- mice did not exhibit any reduction in median survival following radiation. The compound, gallium nitrate, which inhibits IL-1 release in BMDMs, also had no impact on survival of radiated tumor-bearing mice when compared to vehicle-treated mice. These results indicate that an IL-1-based treatment strategy may avoid the deleterious effects of steroids in reducing radiation efficacy while still reducing tumor-associated edema.
Cerebral edema in glioblastoma represents a cause of significant morbidity, with few therapeutic options available. By establishing a new axis by which glioblastoma cells communicate with bone marrow-derived macrophages through the IL-1 signaling pathway, the authors of this study have identified a putative target for modulation of tumor-associated edema. Importantly, their findings that IL-1 knock-out or inhibition does not reduce the efficacy of radiation is a key consideration, given that dexamethasone can impair treatment efficacy. With the recent advent of immunotherapy for glioblastoma, dexamethasone also is under renewed scrutiny, as it induces immunosuppression that may interfere with the efficacy of this therapy. The mechanism by which glioblastoma cells use IL-1 to communicate with BMDMs remains unclear, and future studies should investigate the molecular interactions between glioblastoma cells and BMDMs that lead to aberrant immune infiltration into these tumors.
Financial Disclosure: Neurology Alert’s Editor in Chief Matthew Fink, MD; Peer Reviewer M. Flint Beal, MD; Editorial Group Manager Leslie Coplin; Editor Jason Schneider; Executive Editor Shelly Morrow Mark; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.