The immune microenvironment of high-grade gliomas (HGG) is a complex and heterogeneous system, consisting of diverse cell types such as microglia, bone marrow-derived macrophages (BMDMs), myeloid-derived suppressor cells (MDSCs), dendritic cells, natural killer (NK) cells, and T-cells. Of these, MDSCs are one of the major tumor-infiltrating immune cells and are correlated not only with overall worse prognosis but also poor clinical outcomes. Upon entry from the bone marrow into the peripheral blood, spleen, as well as in tumor microenvironment (TME) in HGG patients, MDSCs deploy an array of mechanisms to perform their immune and non-immune suppressive functions.
Extensive analysis of the immune microenvironment in high-grade glioma (HGG) using single-cell RNA-seq, mass cytometry (CyTOF), immunohistochemistry, flow cytometry, and other “omics” technologies indicate the presence of higher numbers of immune-suppressive macrophages, microglia dendritic cells, regulatory T-cells, and myeloid-derived suppressor cells (MDSCs) . Together, these cells interact with the neoplastic cells to promote tumor growth, progression, metastasis, angiogenesis and contribute to the extreme immunosuppression observed in HGG.
In healthy humans and mice, MDSCs are present at very low frequencies and constitute only ~0.5–2% of peripheral blood mononuclear cells . Nevertheless, 30–50% of the tumor mass in HGGs are found to be MDSCs . Originally, derived from the bone marrow, MDSCs are a very heterogeneous population of immature myeloid cells (IMCs) present at various stages of myelopoiesis. Under normal conditions, IMCs can be differentiated into macrophages, granulocytes, and dendritic cells. However, in pathological conditions such as HGG, the differentiation of IMCs is subverted, resulting in the generation, recruitment, expansion, and activation of MDSCs  not only in the tumor bed but also in the peripheral blood .
In HGGs, MDSCs are derived from the immature myeloid progenitors present in the bone marrow (Figure 1). More recently, single-cell RNA-sequencing (scRNA-seq) analysis on mouse breast tumors suggests that abnormal differentiation of monocyte and neutrophil-like cells in the spleen can lead to the generation of MDSCs . Reprogramming or activation of monocytes and granulocytes by exposure to Toll-like receptors, IL-10, WNT5A, LPS, and INFγ can also give rise to MDSCs . Lastly, MDSCs can be generated and activated ex vivo by the addition of GM-CSF, G-CSF, IL-6, and IL-10 to bone marrow precursors obtained from healthy individuals and detailed functional and phenotypic characterization revealed these bone marrow-derived MDSCs (BM-MDSCs) to be similar to the MDSCs present in different cancer patients .