Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas

Abstract

While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma‐associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H‐non‐mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high‐grade astrocytomas by CD11b‐based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT‐PCR and bioinformatic analyses. A higher amount of CD68‐, CD163‐ and CD206‐positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro‐inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti‐inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2‐like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H‐non‐mutant GBMs.

Development of an Immune Infiltration-Related Prognostic Scoring System Based on the Genomic Landscape Analysis of Glioblastoma Multiforme

“…While M0 can differentiate into M1 and M2 under different stimulations, and they, respectively, exhibit inflammatory response against tumor cells and immunosuppressive response promoting tumor cells proliferation and differentiation (23). However, this concept of dual-polarization status is likely to be oversimplified (24) and is strongly debated (25). In addition, there is a great challenge of this cognition that tumor-related macrophages could co-express M1 and M2 biomarkers and a continuously activated macrophage exists in GBM (25).…”

“…However, this concept of dual-polarization status is likely to be oversimplified (24) and is strongly debated (25). In addition, there is a great challenge of this cognition that tumor-related macrophages could co-express M1 and M2 biomarkers and a continuously activated macrophage exists in GBM (25). More importantly, the function of macrophage will changes quickly when exposure to GBM, leading to innate and adaptive immune suppression (26).…”

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Interestingly, their localization in the tumor appears to depend on their phenotypes Schiffer et al, 2018. In 2012, a meta-analysis showed that a high density of TAMs appeared to be associated with a poor prognosis in head and neck, ovarian and breast cancer and with a better prognosis in colorectal cancer (Zhang et al, 2012;Yuan et al, 2017;Zhao et al, 2017). Further evidence revealed that human GB display a mixed population of M1/M2 macrophages, and the ratio M1:M2 correlated with survival in IDH1 R132H wild type GB (Zeiner et al, 2018). In high-grade gliomas, M2 macrophages were correlated with an unfavorable prognostic (Sørensen et al, 2018).…”

SP1–DLEU1–miR-4429 feedback loop promotes cell proliferative and anti-apoptotic abilities in human glioblastoma

“…According to the World Health Organization (WHO) Pathological Grading Standard (2016 version), glioma is admittedly divided into four grades (I-IV) [35]. Mostly, grade I is identified as benign glioma, while diffuse low-and medium-grade gliomas constitute the WHO grade II and III lesions [36].…”