The hypoxic environment of tumors dictates the phenotype of local myeloid-derived suppressor cells (MDSCs) via HIF-1a expression; hypoxia converts splenic MDSCs from specific into nonspecific suppressors.
Myeloid derived suppressor cells (MDSCs) are one of the main cell populations responsible for regulating immune responses. MDSCs accumulate during tumor progression, autoimmunity, chronic infection and other pathological conditions and can potently suppress T cell function. Recent studies have demonstrated the ability of MDSCs to modulate the activity of NK and myeloid cells and have implicated MDSCs in the induction of regulatory T cells. In this review we discuss recent findings that describe the molecular mechanisms that regulate expansion and function of MDSCs, as well as recent attempts to use MDSCs in cell therapy for different pathologic conditions. Myeloid-derived suppressor cells (MDSCs) as negative regulators of immune responsesMDSC represent a heterogenic population of immature myeloid cells that consists of myeloid progenitors and precursors of macrophages, granulocytes, and dendritic cells (DC) and are characterized by a strong ability to suppress various T-cell functions [1]. In mice, MDSCs are identified as cells that simultaneous express two markers: CD11b and Gr-1 1 . More recently, MDSCs were subdivided into two different subsets based on their expression of the two molecules Ly-6C and Ly-6G, which can be detected by specific antibodies [2,3]. CD11b + Ly-6G − Ly-6C high cells have monocytic-like morphology and are termed monocytic-MDSCs (M-MDSCs). CD11b + Ly-6G + Ly-6C low cells have granulocyte-like morphology and are termed granulocytic-MDSCs (G-MDSCs). In cancer patients, MDSCs are defined as cells that express the common myeloid marker CD33 but lack expression of markers of mature myeloid and lymphoid cells [4]. In recent years, more markers were associated with MDSC function in humans. A monocytic MDSC with the phenotype CD14 + CD11b + HLA-DR low/neg has been detected in melanoma patients [5,6]. In patients with melanoma and colon carcinomas, two main subpopulations functionally suppress the immune response: CD14 + monocytes and CD15 + neutrophils both expressing IL-4 receptor (CD124) [7]. MDSCs are also defined as CD11b + CD14 − CD15 + CD33 + cells in patients with advanced non-small cell lung cancer [8,9]. MDSCs from patients with renal cell cancer, express markers of activated granulocytes, including high levels of CD66b and low levels of
Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 OLR1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5–15% of total neutrophils in cancer patients and 15–50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1− counterparts, LOX-1+ neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.
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