Ntigen-driven anti-tumor immunity. However, factors produced by the tumor and its

Ntigen-driven anti-tumor immunity. However, factors produced by the tumor and its

Ntigen-driven anti-tumor immunity. However, factors produced by the tumor and its microenvironment can abrogate anti-tumor immunity and facilitate local spread and metastasis. The balance between immune responses that inhibit versus facilitate tumor growth can predict clinical outcome. Therapeutic targeting of immune pathways that facilitate tumor escape may extend periods of disease-free 57773-65-6 site progression and, potentially, overcome barriers to durable anti-tumor immunity. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are 10457188 recruited by cancer cells and can accumulate both locally and systemically in advanced cancer. Mouse MDSCs are a heterogeneous myeloid population consisting of CD11b+Gr1+ cells. The two major MDSC sub-populations, granulocytic and monocytic, are defined based on the expression of Ly6G and Ly6C, the components of Gr1, and by their immunosuppressive activity. Granulocytic MDSCs are CD11b+Ly6G+Ly6Clow/neg and monocytic MDSCs are CD11b+Ly6GnegLy6Chigh [1,2]. MDSCs can suppress anti-tumor responses through several mechanisms: suppression of CD4+ and CD8+ T cells by arginine and cysteine depletion, PLV-2 inhibition of T cell recruitment to tumor sites, inhibition of T cell-peptide-MHC interactions, skewing of the cytokine milieu toward type 2 or regulatory responses, and modulating NK and NKT responses [3?13]. In addition to their immunosuppressive properties, MDSCs can secrete factors (e.g., vascular endothelial growth factor (VEGF)) that enhance tumor growth, invasion, and metastasis [5,14]. Epithelial ovarian cancer (EOC) is typically diagnosed at advanced stages. Even with optimal surgical debulking and chemotherapy, the vast majority of patients with advanced EOC will have progression of disease. However, there is considerableMyeloid-Derived Suppressor Cells and NADPH Oxidasevariability in progression-free survival and overall survival among patients with advanced EOC [15]. The role of immune surveillance in EOC was demonstrated by correlation of survival with tumor-infiltrating lymphocytes (TILs) [16]. Intraepithelial CD8+ TILs and a high CD8+/Treg ratio were associated with favorable prognosis in patients with EOC [17,18]. Changes in the phenotype of tumor-infiltrating DCs influence EOC progression in mice [19]. MDSCs accumulate in the ascites of patients with advanced EOC and suppress T cell proliferation ex vivo [20]. These findings raise the potential for MDSCs in the EOC microenvironment as potential therapeutic targets. It is therefore important to understand mechanisms that lead to expansion and functional properties of MDSCs. There is growing evidence that reactive oxidant intermediates (ROIs) and reactive nitrogen intermediates modulate the development of MDSCs. NADPH oxidase (NOX2) is the major source of ROIs in activated phagocytes. NADPH oxidase activation requires translocation of the cytoplasmic subunits p47phox, p67phox, and p40phox and rac to the membrane-bound flavocytochrome consisting of gp91phox and p22phox (phox, phagocyte oxidase). Following activation, NADPH oxidase converts molecular oxygen to superoxide anion that can be subsequently converted to downstream ROI metabolites (e.g., hydrogen peroxide). NADPH oxidase is critical for antimicrobial host defense and also modulates inflammatory responses [21]. Prior studies in mice have shown that NOX2 enhances MDSC differentiation and function [22,23]. In the absence of NADPH oxidase, MDSCs lacked the abili.Ntigen-driven anti-tumor immunity. However, factors produced by the tumor and its microenvironment can abrogate anti-tumor immunity and facilitate local spread and metastasis. The balance between immune responses that inhibit versus facilitate tumor growth can predict clinical outcome. Therapeutic targeting of immune pathways that facilitate tumor escape may extend periods of disease-free progression and, potentially, overcome barriers to durable anti-tumor immunity. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are 10457188 recruited by cancer cells and can accumulate both locally and systemically in advanced cancer. Mouse MDSCs are a heterogeneous myeloid population consisting of CD11b+Gr1+ cells. The two major MDSC sub-populations, granulocytic and monocytic, are defined based on the expression of Ly6G and Ly6C, the components of Gr1, and by their immunosuppressive activity. Granulocytic MDSCs are CD11b+Ly6G+Ly6Clow/neg and monocytic MDSCs are CD11b+Ly6GnegLy6Chigh [1,2]. MDSCs can suppress anti-tumor responses through several mechanisms: suppression of CD4+ and CD8+ T cells by arginine and cysteine depletion, inhibition of T cell recruitment to tumor sites, inhibition of T cell-peptide-MHC interactions, skewing of the cytokine milieu toward type 2 or regulatory responses, and modulating NK and NKT responses [3?13]. In addition to their immunosuppressive properties, MDSCs can secrete factors (e.g., vascular endothelial growth factor (VEGF)) that enhance tumor growth, invasion, and metastasis [5,14]. Epithelial ovarian cancer (EOC) is typically diagnosed at advanced stages. Even with optimal surgical debulking and chemotherapy, the vast majority of patients with advanced EOC will have progression of disease. However, there is considerableMyeloid-Derived Suppressor Cells and NADPH Oxidasevariability in progression-free survival and overall survival among patients with advanced EOC [15]. The role of immune surveillance in EOC was demonstrated by correlation of survival with tumor-infiltrating lymphocytes (TILs) [16]. Intraepithelial CD8+ TILs and a high CD8+/Treg ratio were associated with favorable prognosis in patients with EOC [17,18]. Changes in the phenotype of tumor-infiltrating DCs influence EOC progression in mice [19]. MDSCs accumulate in the ascites of patients with advanced EOC and suppress T cell proliferation ex vivo [20]. These findings raise the potential for MDSCs in the EOC microenvironment as potential therapeutic targets. It is therefore important to understand mechanisms that lead to expansion and functional properties of MDSCs. There is growing evidence that reactive oxidant intermediates (ROIs) and reactive nitrogen intermediates modulate the development of MDSCs. NADPH oxidase (NOX2) is the major source of ROIs in activated phagocytes. NADPH oxidase activation requires translocation of the cytoplasmic subunits p47phox, p67phox, and p40phox and rac to the membrane-bound flavocytochrome consisting of gp91phox and p22phox (phox, phagocyte oxidase). Following activation, NADPH oxidase converts molecular oxygen to superoxide anion that can be subsequently converted to downstream ROI metabolites (e.g., hydrogen peroxide). NADPH oxidase is critical for antimicrobial host defense and also modulates inflammatory responses [21]. Prior studies in mice have shown that NOX2 enhances MDSC differentiation and function [22,23]. In the absence of NADPH oxidase, MDSCs lacked the abili.

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