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


The cover for issue 33 of Oncotarget features Figure 5, "Microglia and macrophages are more pro-inflammatory in IDH-MUT compared to IDH-WT GBMs," by Poon, et al.

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.

Using flow cytometry, immunofluorescence techniques with automated segmentation protocols that quantify at the individual-cell level, and comparison between single-cell RNA-sequencing databases of human GBM, the authors discerned dissimilarities between GBM-associated microglia and macrophages in IDH-mutant and -wild type GBMs. They 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.

Dr. John J.P. Kelly from the Department of Clinical Neurosciences at the University of Calgary, in Calgary, AB, Canada, and corresponding author of the paper, said, "Glioblastoma (GBM) is the most common adult brain cancer with a median survival of 14.6 months despite aggressive surgery and chemoradiation."

Figure 1: Schematic of methodology.

Single-cell RNA sequencing studies of human GBM, in agreement with more classical immunohistochemical studies, have shown that the predominant immune cell type in the tumor microenvironment are myeloid cells comprised of microglia and macrophages.

It has been suggested that microglia and macrophages within GBM initially participate in tumor surveillance, but are subverted by GBM to adopt grossly anti-inflammatory phenotypes and subsequently promote immunosuppression, tumor angiogenesis and invasion.

The majority of GAMM research has been in isocitrate dehydrogenase-wild type GBMs. In 2016, the World Health Organization Classification of Tumors of the Central Nervous System was revamped to divide GBM into three major categories: IDH-WT, IDH-mutant, and IDH not otherwise specified.

However, studies of untreated IDH-MUT GAMMs are rare because not only do IDH-MUT GBMs account for approximately 10% of GBMs, but they almost always present first as lower grade gliomas which are treated with surgery and chemoradiation, processes which can drastically alter the native phenotype of microglia and macrophages.

They hypothesized that not only will there be heterogeneity in the microglia and macrophage response between GBMs, but that microglia and macrophages in IDH-MUT tumors differ from those in wild type tumors.

Then the Kelly Research Team concluded, "The phenotype of GAMM differs between IDH-WT and -MUT GBMs. Our results show this novel distinction at the protein level in rare untreated human IDH-MUT GBMs and at the single-cell RNA level through public databases.

Increased microglia and macrophage pro-inflammatory activation may help explain why GBM patients with IDH mutations fare better than those without."

Full text - https://doi.org/10.18632/oncotarget.26863

Correspondence to - John J.P. Kelly - [email protected]

Keywords - glioblastoma, microglia, macrophages, isocitrate dehydrogenase, single-cell RNA sequencing

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