Tumour‐associated microglia/macrophages predict poor prognosis in high‐grade gliomas and correlate with an aggressive tumour subtype

Abstract

(2018) Neuropathology and Applied Neurobiology 44, 185-206 Tumour-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumour subtype Aims: Glioblastomas are highly aggressive and treatment resistant. Increasing evidence suggests that tumour-associated macrophages/microglia (TAMs) facilitate tumour progression by acquiring a M2-like phenotype. Our objective was to investigate the prognostic value of TAMs in gliomas using automated quantitative double immunofluorescence. Methods: Samples from 240 patients with primary glioma were stained with antibodies against ionized calcium-binding adaptor molecule-1 (IBA-1) and cluster of differentiation 204 (CD204) to detect TAMs and M2-like TAMs. The expression levels were quantified by software-based classifiers. The associations between TAMs, gemistocytic cells and glioblastoma subtype were examined with immuno-and haematoxylin-eosin stainings. Three tissue arrays containing glioblastoma specimens were included to study IBA-1/CD204 levels in central tumour and tumour periphery and to characterize CD204 + cells. Results: Our data revealed that the amount of especially CD204 + TAMs increases with malignancy grade. In grade III-IV, high CD204 expression was associated with shorter survival, while high IBA-1 intensity correlated with a longer survival. In grade IV, CD204 showed independent prognostic value when adjusting for clinical data and the methylation status of O6-methylguanine-DNA methyltransferase. Our findings were confirmed in two bioinformatics databases. TAMs were more abundant in central tumour tissue, mesenchymal glioblastomas and gliomas with many gemistocytic cells. CD204 + TAMs coexpressed proteins related to tumour aggressiveness including matrix metallopeptidase-14 and hypoxiainducible factor-1a. Conclusions: This is the first study to use automated quantitative immunofluorescence to determine the prognostic impact of TAMs. Our results suggest that M2-like TAMs hold an unfavourable prognostic value in high-grade gliomas and may contribute to a pro-tumourigenic microenvironment.

AVNP2 protects against cognitive impairments induced by C6 glioma by suppressing tumour associated inflammation in rats

“…They aggregate in and around glioma tissue and participate in the proliferation and invasion of tumour cells (Noy and Pollard, 2014;Wu and Watabe, 2017). There exists a positive correlation between the level of inflammatory cytokines inside the tumour micro-environment (TME) and the poor clinical prognosis of patients (Sorensen et al, 2018). Modulating the local inflammatory response has become a new strategy for immunotherapy due to its vital role in the development of tumours (Graf et al, 2002;Mineharu et al, 2011).…”

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

“…The malignant phenotype of GB is supported by a favorable microenvironment which it orchestrates through an active secretome. Tumor‐associated macrophages and microglia (TAMs), which make up as much as 40% of the cellular content in GB, are recruited by chemoattractants that are produced by the tumor cell (Chen & Hambardzumyan, ; Hambardzumyan, Gutmann, & Kettenmann, ; Sorensen, Dahlrot, Boldt, Hansen, & Kristensen, ). TAMs are then induced by the tumor to produce soluble factors such as IL‐6, IL‐1, TGF‐β, and matrix metalloproteinases (MMPs) which enhance the motility, invasion, angiogenesis, and proliferation of both GB cells and glioma stem cells.…”

“…induced to suppress anti-tumor immune cells through production of factors such as TGF-β and PD-L1 (Hambardzumyan et al, 2016;Noguchi et al, 2017;Sun, Mezzadra, & Schumacher, 2018). The positive influence of TAMs on GB progression is underscored by clinicopathological data associating higher tumor grade and worse prognosis with increasing populations of TAMs (Sorensen et al, 2018). The molecular response of TAMs to paracrine factors released by glioma cells is clearly complex and involves numerous signaling pathways and transcriptional factors such as STATs and NF-ĸB, (Holtman, Skola, & Glass, 2017;Li & Graeber, 2012).…”

Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

“…Male patients had more IBA1+ and CD204+ cells in their tumors based on the immunohistochemistry staining ( Fig. 5A), suggesting an increase in the immunosuppressive myeloid cell population 29 . Analysis of a separate cohort of male patients revealed that mMDSCs were the prevalent subset in human GBM tissue ( Fig.…”

“…Specimens from 188 patients with a primary glioma diagnosis were stained with ionized calcium-binding adaptor molecule-1 (IBA-1) and cluster of differentiation 204 (CD204) 29 . The published dataset was reanalyzed by accounting for patient sex, and the IBA-1 and CD204 staining intensities were graphed separately for male versus female patients.…”