Oncotarget

Research Papers:

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

Candice C. Poon, Paul M.K. Gordon, Katherine Liu, Runze Yang, Susobhan Sarkar, Reza Mirzaei, Shiekh Tanveer Ahmad, Martha L. Hughes, V. Wee Yong and John J.P. Kelly _

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Oncotarget. 2019; 10:3129-3143. https://doi.org/10.18632/oncotarget.26863

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Abstract

Candice C. Poon1, Paul M.K. Gordon2, Katherine Liu1, Runze Yang1, Susobhan Sarkar1, Reza Mirzaei1, Shiekh Tanveer Ahmad3, Martha L. Hughes1, V. Wee Yong1,* and John J.P. Kelly1,*

1Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada

2Centre for Health Genomics and Informatics, University of Calgary, Calgary, AB, Canada

3Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada

*These authors contributed equal supervision to this work

Correspondence to:

John J.P. Kelly, email: jjkelly@ucalgary.ca

Keywords: glioblastoma; microglia; macrophages; isocitrate dehydrogenase; single-cell RNA sequencing

Received: January 11, 2019     Accepted: March 04, 2019     Published: May 03, 2019

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.


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