TMIC-18TUMOR-ASSOCIATED MICROGLIA/MACROPHAGES ARE ASSOCIATED WITH POOR PROGNOSIS IN HIGH-GRADE GLIOMAS AND CONTRIBUTE TO THE GLIOBLASTOMA STEM CELL-LIKE NICHES

Abstract

BACKGROUND: In glioblastomas tumor-associated microglia/macrophages (TAMs) constitute up to 30% of the tumor. TAMs can interact with glioblastoma stem-like cells (GSC) and favor progression by acquiring a protumorigenic M2 phenotype. The aims of this study were to investigate the prognostic impact of TAMs in gliomas and the physical interaction between TAMs and GSC in situ in glioblastomas. METHODS: Using automated quantitative double immunofluorescence 242 patient samples were stained with anti-IBA-1 and anti-CD204 to detect TAMs and M2 TAMs, respectively. Area fractions (AF) of IBA-1 and CD204 in total tissue and of CD204 within the IBA-1+ area were obtained by software classifiers (i.e. IBA-1(total), CD204(total), and CD204(IBA-1)). The interplay between TAMs and GSC was examined on 10 glioblastomas with double immunohistochemistry using IBA-1 and stem cell markers. RESULTS: Our results showed that IBA-1(total),CD204(total) andCD204(IBA-1) increased with grade (p < 0.0001). In univariate analyses, high CD204(total) (HR 3.96 95%CI 1.57-10.03, p = 0.004) and CD204(IBA-1) (HR 2.86, 95%CI 1.17-6.97, p = 0.021) were associated with shorter survival in grade III tumors. Similar was found for CD204(total) (HR 1.38 95%CI 1.02-1.85, p = 0.035) in grade IV tumors. In multivariate analyses, high CD204(total) was associated with poorer survival (HR 3.18, 95%CI 1.03-9.81, p = 0.045) in grade III tumors. In grade IV tumors CD204(total) (HR 1.70, 95%CI 1.24-2.33, p = 0.001) had independent prognostic value, and similar tendency was observed for CD204(IBA-1) (HR 1.19, 95%CI 0.87-1.63, p = 0.27). IBA-1(total) was insignificant regarding prognosis in all grades. In glioblastomas TAMs and GCS, especially CD133+ and podoplanin+ cells, accumulated around vessels and necroses. Further, the density of GSC tended to be higher around TAMs in these areas indicating an interaction between the two populations. CONCLUSIONS: Our results suggest that TAMs are important in the tumor microenvironment and contribute to glioma stemness and aggressiveness possibly explained by their M2 polarization which has prognostic impact in high-grade gliomas.