Differential microglia and macrophage profiles in human IDH-mutant and -wild type glioblastoma

Abstract

Microglia and macrophages are the largest component of the inflammatory infiltrate in glioblastoma (GBM). However, whether there are differences in their representation and activity in the prognostically-favorable isocitrate dehydrogenase (IDH)-mutated compared to -wild type GBMs is unknown. Studies on human specimens of untreated IDH-mutant GBMs are rare given they comprise 10% of all GBMs and often present at lower grades, receiving treatments prior to dedifferentiation that can drastically alter microglia and macrophage phenotypes. We were able to obtain large samples of four previously untreated IDH-mutant GBM. Using flow cytometry, immunofluorescence techniques with automated segmentation protocols that quantify at the individual-cell level, and comparison between single-cell RNA-sequencing (scRNA-seq) databases of human GBM, we discerned dissimilarities between GBM-associated microglia and macrophages (GAMMs) in IDH-mutant and -wild type GBMs. We found there are significantly fewer GAMM in IDH-mutant GBMs, but they are more pro-inflammatory, suggesting this contributes to the better prognosis of these tumors. Our pro-inflammatory score which combines the expression of inflammatory markers (CD68/HLA-A, -B, -C/TNF/CD163/IL10/TGFB2), Iba1 intensity, and GAMM surface area also indicates that more pro-inflammatory GAMMs are associated with longer overall survival independent of IDH status. Interrogation of scRNA-seq databases demonstrates microglia in IDH-mutants are mainly pro-inflammatory, while anti-inflammatory macrophages that upregulate genes such as FCER1G and TYROBP predominate in IDH-wild type GBM. Taken together, these observations are the first head-to-head comparison of GAMMs in treatment-naïve IDH-mutant versus -wild type GBMs. Our findings highlight biological disparities in the innate immune microenvironment related to IDH prognosis that can be exploited for therapeutic purposes.

Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas

“…However, most studies show that, despite being well tolerated, immunotherapy failed to prolong GBM patient survival [ 149 ], perhaps because it focused on T-cells, which are sparse in GBM [ 150 , 151 , 152 ]. More recently, an association between the IDH1/2 mutations profile and the macrophagic subsets in GBM has pointed to macrophages and microglia as useful players in new immunotherapeutic approaches [ 153 ].…”

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

“…Surrounding BTICs in situ are microglia, which are innate immune cells of the CNS and macrophages that have infiltrated as monocytes from the circulation (13)(14)(15)(16). These cells are thought to be initially recruited to eradicate the tumor by stimulating apoptosis of glioma cells (17) and by secreting inflammatory factors that prevent glioma growth and invasiveness (18).…”

Computational approach to identifying universal macrophage biomarker

“…Literature review showed a computational approach named correlation-based feature subset (CFS) identified TYROBP as part of the hub genes in kidney cancer samples using protein-protein interaction network 63 . Another study reported that microglia in IDH-mutants are mainly pro-inflammatory, while anti-inflammatory macrophages that upregulate genes such as FCER1G and TYROBP predominate in IDH-wild type GBM 64 . Tyrobp and Fcer1g was found to be differentially expressed in Alzheimer’s disease (AD) mouse models that demonstrated strong correlation between cortical Aβ amyloidosis and the neuroinflammatory response 65 .…”