Glioma Grade Is Associated with the Accumulation and Activity of Cells Bearing M2 Monocyte Markers

Abstract

Purpose: This study is directed at identifying the cell source(s) of immunomodulatory cytokines in highgrade gliomas and establishing whether the analysis of associated markers has implications for tumor grading.Experimental Design: Glioma specimens classified as WHO grade II-IV by histopathology were assessed by gene expression analysis and immunohistochemistry to identify the cells producing interleukin (IL)-10, which was confirmed by flow cytometry and factor secretion in culture. Finally, principal component analysis (PCA) and mixture discriminant analysis (MDA) were used to investigate associations between expressed genes and glioma grade.Results: The principle source of glioma-associated IL-10 is a cell type that bears phenotype markers consistent with M2 monocytes but does not express all M2-associated genes. Measures of expression of the M2 cell markers CD14, CD68, CD163, and CD204, which are elevated in high-grade gliomas, and the neutrophil/myeloid-derived suppressor cell (MDSC) subset marker CD15, which is reduced, provide the best index of glioma grade.Conclusions: Grade II and IV astrocytomas can be clearly differentiated on the basis of the expression of certain M2 markers in tumor tissues, whereas grade III astrocytomas exhibit a range of expression between the lower and higher grade specimens. The content of CD163 þ cells distinguishes grade III astrocytoma subsets with different prognosis.

Ceacam1L Modulates STAT3 Signaling to Control the Proliferation of Glioblastoma-Initiating Cells

“…S6). It has been shown that CD68 þ cells increased in high-grade gliomas (48), and that CD68 þ infiltrating microglias/macrophages were involved in gliomagenesis (49). Together, these suggest that CD68 þ microglias/macrophages play a crucial part to maintain/activate GICs in the niche.…”

CD68/macrosialin: not just a histochemical marker

“…TAMs acquire immunosuppressive properties and inhibit cytotoxic activity of CD8 + T cells in tumors. 75 A population of CD68-positive immature myeloid cells (called myeloid-derived suppressor cells (MDSCs) that inhibit proliferation and cytokine release by T cells was found to be present in glioma 76 and squamous cell carcinoma tumors. 77 These cells can be produced by the tumor microenvironment from circulating monocytes.…”

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…18,19 Gliomas have been shown to employ a variety of mechanisms to suppress the immune system, such as downregulation of MHC class I molecules, production of transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), prostaglandin E2, and IL-10, expression of ligands of checkpoint receptors, such as PD-1, and accumulation of immunosuppressive cells, such as myeloidderived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs). [23][24][25][26][27][28][29][30] It has been previously shown in human samples and experimental GBM models that MDSCs are powerful inhibitors of anti-tumor immune responses. 30,31 Through a variety of mechanisms that inhibit T cell activation and expansion, including the production of arginase and inducible nitric oxide synthase (iNOS), reactive oxygen species and/or reactive nitrogen species (ROS and/or RNS), release of IL-10, expansion of regulatory T cells (Tregs), and inhibition of T cell migration, MDSCs have been shown to promote immunosuppression and tumor progression.…”