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 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.