GP.06 Differential microglia and macrophage profiles in human IDH-mutant and -wildtype glioblastoma reveal therapeutic vulnerabilities. (June 2019)

• Record Type: Journal Article
• Authors: Poon, CC; Gordon, P; Liu, K; Yang, R; Sarkar, S; Yong, VW; Kelly, J
• Is Part Of: Canadian journal of neurological sciences. Volume 46(2019)Supplement 1
• Page Start: S7
• Page End: S7
• Publication Date: 2019-06
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Electronic journals; 616.8
• DOI: 10.1017/cjn.2019.82
• Languages: English
• ISSNs: 0317-1671

Abstract

Abstract : Background: Microglia and macrophages (MMs) are the largest component of the inflammatory infiltrate in glioblastoma (GBM). However, whether there are immunophenotypic differences in isocitrate dehydrogenase (IDH)-mutated and -wildtype GBMs is unknown. Studies on specimens of untreated IDH-mutant GBMs are rare given they comprise 10% of all GBMs and often receive treatment at lower grades that can drastically alter MM phenotypes. Methods: We obtained large samples of untreated IDH-mutant and -wildtype GBMs. Using immunofluorescence techniques with single-cell automated segmentation, and comparison between single-cell RNA-sequencing (scRNA-seq) databases of human GBM, we discerned dissimilarities between GBM-associated MMs (GAMMs). Results: There are significantly fewer but more pro-inflammatory GAMMs in IDH-mutant GBMs, 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 more pro-inflammatory GAMMs are associated with longer overall survival independent of IDH status. scRNA-seq analysis demonstrates microglia in IDH-mutants are mainly pro-inflammatory, while anti-inflammatory macrophages that upregulate genes such as FCER1G and TYROBP predominate in IDH-wildtype GBM. Conclusions: Taken together, these observations are the first head-to-head comparison of GAMMs in treatment-naïve IDH-mutant versus -wildtype GBMs that highlight biological disparities that can be exploited for therapeutic purposes.