Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprechts-Karls-University Heidelberg
Tumor-associated macrophages (TAMs) play an emerging role in tumor progression by creating an immunosuppressive tumor microenvironment. Therefore, we investigated TAM numbers and their activation (M1/2) in primary (p‑) and recurrent (r‑) meningiomas and evaluated their impact on survival. Presence of TAMs was analyzed in 195 clinically well-annotated cases (WHO°I n = 43, WHO°II n = 95, WHO°III n = 57; pMGM n = 120, rMGM n = 75). TAMs were quantified by a semiautomated analysis on whole tissue sections stained by multicolor immunofluorescence for CD68 as general TAM marker, and for CD163 and CD204 as M2 marker. CD68+ macrophages positive for either CD163 or CD204 were regarded as M2-polarized TAMs. Furthermore, concentration of 27 immune-relevant cytokines and chemokines from meningioma tissue samples (n = 46) were assessed by Luminex analysis. Median TAM infiltration accounted for 2.47% per total cell count in pMGM and 3.22% in rMGMs. Although no significant WHO°‑dependent changes regarding TAM numbers were observed, high numbers of TAMs were associated with shorter progression‑free survival (PFS) independent of prognostic confounding variables such as WHO, sex and age. In pMGMs, proportion of M2‑polarized TAMs was significantly increased in WHO°II and WHO°III tumors compared to WHO°I (P = 0.001 and P = 0.03, respectively). Luminex data revealed a WHO°‑dependent increase of IL‑8, IL‑10, and IL‑12p70. Tissue samples containing higher numbers of TAMs demonstrated significant elevated concentrations of interleukin‑1 family members (IL-1β, IL-1Ra), and G-CSF. Furthermore, upregulation of IL-1β and IL-1Ra resulted in shorter overall survival of patients (P = 0.049, P = 0.006, respectively). Taken together, we identified higher numbers of TAMs as an independent prognostic factor for shorter progression-free survival in meningioma patients. This was associated with increased levels of the interleukin-1 family members IL-1β and IL-1Ra and a shorter overall survival, indicating an important function in the tumor microenvironment.