The role of the tumor microenvironment in cerebral glioma progression

Background: The tumor associated macrophages (TAMs) are classified into pro-inflammatory M1 TAMs, and anti-inflammatory M2 TAMs. Glioma stem cells (GSCs) polarize TAMs into M2 phenotype which promote glioma progression. We aimed to study the implication of the total and differential TAM infiltration in low grade glioma (LGG) and high grade glioma (HGG). Also we investigated the effect of exosomes released from M1 TAMs on the fate of glioma cells. Methodolgy: Immunohistochemistry was performed on 11 paired specimens obtained from cases progressing from LGG to HGG. iNOS was used as a marker for M1 and CD163 as a marker for M2. In the in-vitro experiments, we polarized human monocytes U937 into M1 phenotype, then we isolated the exosomes from the M1conditioned medium by centrifugation and filtration. After adding M1 exosomes to U251 glioma cells, we studied the glioma cell activation by MTT assay and we studied the glioma cell apoptosis by flow-cytometry. We used Annexin V as a marker of early apoptosis and propidium iodide as a marker of late apoptosis. Results: immunohistochemistry showed an M1/M2 imbalance with the majority being M2 in either LGG and HGG. The higher M2 infiltration, the earlier was the progression. The in-vitro experiments revealed the anti-tumor effect of M1 exosomes which were able to inhibit the proliferation and to induce early and late apoptosis of glioma cells. Conclusion: our data confirmed the role of M2 TAMs in glioma progression and exhibited the tumoricidal role of M1 exosomes against gliomas.