Abstract
Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors.
Highlights
Tumor-associated stromal cells like endothelial, mesenchymal and infiltrating inflammatory cells play an important role in tumor pathogenesis
myeloid-derived suppressor cells (MDSC), do not represent a single cell population, but are composed of immature myeloid cells at different stages of cell differentiation. These cells can suppress the immune response by several mechanisms, including the production of arginase 1 (Arg1), which decreases the level of L-arginine that is critical for normal T cell function
Immunohistochemical stains were performed on 4 μm sections cut from formalin-fixed and paraffin embedded tumor (FFPET) blocks and stained with a rabbit anti-human Arg1 monoclonal antibody (Clone SP156, BD Transduction Laboratories) at 1:1500 dilution following a 30 minute steam retrieval in DEVA buffer
Summary
Tumor-associated stromal cells like endothelial, mesenchymal and infiltrating inflammatory cells play an important role in tumor pathogenesis. MDSCs, do not represent a single cell population, but are composed of immature myeloid cells at different stages of cell differentiation These cells can suppress the immune response by several mechanisms, including the production of arginase 1 (Arg1), which decreases the level of L-arginine that is critical for normal T cell function. Evaluation of human tumor specimen confirmed Arg expression in both TAMs and other myeloid-derived cells such as neutrophils These findings confirm dynamic changes in TAM polarization that is dependent on tumor microenvironmental factors and highlights variations in the contribution of MDSCs to the immunosuppressive glioma milleu
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