title: Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells.
abstract: 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) and such diverse COX2 activators as lipopolysaccharide, IL-1β, and IFNγ all induce monocyte expression of COX2, blocking their differentiation into CD1a(+) DCs and inducing endogenous PGE(2), IDO1, IL-4Rα, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE(2) to GM-CSF/IL-4-supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)-suppressive function. In accordance with the key role of PGE(2) in the physiologic induction of human MDSCs, the frequencies of CD11b(+)CD33(+) MDSCs in ovarian cancer are closely correlated with local PGE(2) production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE(2) feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients. The central role of COX2-PGE(2) feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity, or transplantation.
authors.affiliation: Department of Surgery, University of Pittsburgh,Hillman Cancer Center, UPCI Research Pavilion, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.
authors.forename: Natasa
authors.initials: N
authors.lastname: Obermajer
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Muthuswamy
authors.forename: Jamie
authors.initials: J
authors.lastname: Lesnock
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001201:Ascites / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D018950:Lipopolysaccharide Receptors; C545644:PTGER2 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D063268:Sialic Acid Binding Ig-like Lectin 3; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone