Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. In the present study, we report that the establishment of a positive feedback loop between prostaglandin E 2 (PGE 2 ) and cyclooxygenase 2 (COX2), the key regulator of PGE 2 synthesis, represents the determining factor in redirecting the development of CD1a ؉ DCs to CD14 ؉ CD33 ؉ CD34 ؉ monocytic MDSCs. Exogenous PGE 2 IntroductionDendritic cells (DCs) are key initiators and regulators of immune responses. [1][2][3] Whereas the suppression of endogenous DC function has been shown to contribute to cancer progression, therapeutic targeting of DCs to suppress their function has been shown to be beneficial in mouse models of autoimmunity or transplantation. 4 In contrast to DCs, myeloid-derived suppressor cells (MDSCs) suppress the ability of CD8 ϩ T cells to mediate effective responses against cancer cells, but can be beneficial in controlling autoimmune phenomena or transplantation rejection. [5][6][7] MDSCs express CD34, common myeloid marker CD33, macrophage/DC marker CD11b, and IL-4R␣ (CD124), but lack expression of the lineage (Lin) markers of DCs and other mature myeloid cells. 7,8 Human MDSCs are defined as CD33 ϩ Lin Ϫ HLA-DR Ϫ/low or CD33 ϩ CD14 Ϫ HLA-DR Ϫ , with recent studies demonstrating a CD14 ϩ CD11b ϩ HLA-DR low phenotype of monocytic MDSCs in melanoma, 9 prostate cancer, 10 gastrointestinal malignancies, 11 hepatocellular carcinoma, 12,13 and glioblastoma, 14 in addition to a CD15 ϩ population of neutrophil-related immature MDSCs of similar biologic activity present in the peripheral blood. 7 MDSCs express high levels of immunosuppressive factors such as indoleamine dioxygenase (IDO), 15,16 8 arginase, 17,18 inducible nitric oxide synthase (NOS2), 18 nitric oxide, and reactive oxygen species, 19 and use these molecules to suppress T-cell responses, 20,21 whereas their induction of natural killer cell anergy and reduced cytotoxicity is arginase independent 12 but depends on TGF␤ 1. 22 In addition, PD-L1/B7-H1, which is induced on MDSCs in the tumor microenvironment, 23,24 suppresses antigen-specific immunity by activating regulatory T cells 23 and reduces tumor clearance via enhanced T-cell IL-10 expression and reduced IFN-␥ production. 24 Molecular pathways involved in negative regulation of DC function remain largely unknown; however, they may involve the induction of the myeloid cell-expressed inhibitory immunoglobulinlike transcript receptors ILT-3 and ILT-4, which negatively regulate the activation of DCs, promoting T-cell tolerance. 25,26 The development of functional MDSCs requires the inhibition of immunostimulatory APC development and the concomitant induction of suppressive functions. 5 Such factors as GM-CSF, IL-6, or VEGF promote the expansion of immature myeloid cells (iMCs). 20,[27][28][29] An additional signal is required for the up-regulation of MDSC-associated immunosuppressive factors and for the establishment of their immunosuppressive function. Paradoxically, this signa...

Signals mediated by CXCL12 (SDF1) and its receptor CXCR4 are centrally involved in cancer progression, both directly by activating cancer cells and indirectly by inducing angiogenesis plus recruiting T regulatory and plasmacytoid dendritic immune cells. Here, we show that in ascites isolated from ovarian cancer patients, both CXCL12 and CXCR4 are controlled by the tumor-associated inflammatory mediator prostaglandin E2 (PGE2), which attracts myeloid-derived suppressor cells (MDSC) into the ascites microenvironment. In this setting, PGE2 was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b+CD14+CD33+CXCR4+ MDSCs closely correlated with CXCL12 and PGE2 levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE2 production. Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. Similarly, COX2 inhibition also blocked CXCL12 production in the ovarian cancer environment and its ability to attract MDSCs. Together, our findings elucidate a central role for PGE2 in MDSC accumulation triggered by the CXCL12-CXCR4 pathway, providing a powerful rationale to target PGE2 signaling in ovarian cancer therapy.

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