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

M D Sørensen, R H Dahlrot, H B Boldt, S Hansen, B W Kristensen

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Abstract

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 co-expressed proteins related to tumour aggressiveness including matrix metallopeptidase-14 and hypoxia-inducible factor-1α.

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.

Original languageEnglish
JournalNeuropathology and Applied Neurobiology
Volume44
Issue number2
Pages (from-to)185-206
ISSN0305-1846
DOIs
Publication statusPublished - Feb 2018

Keywords

  • Journal Article
  • macrophages
  • glioblastoma
  • glioma
  • CD204
  • microglia
  • prognosis
  • O(6)-Methylguanine-DNA Methyltransferase/metabolism
  • Glioma/metabolism
  • Microglia/metabolism
  • Prognosis
  • Humans
  • Macrophages/metabolism
  • Male
  • Survival Rate
  • Brain Neoplasms/metabolism
  • DNA Methylation
  • Tumor Microenvironment/physiology
  • Female

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