title: PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells.
abstract: Myeloid-derived suppressor cells (MDSCs) are critical mediators of tumor-associated immune suppression, with their numbers and activity strongly increased in most human cancers and animal models. MDSCs suppress anti-tumor immunity through multiple mechanisms, including the manipulation of arginine and tryptophan metabolism by such factors as arginase (Arg), inducible nitric oxide synthase (iNOS/NOS2), and indoleamine-2,3-dioxygenase (IDO). Prostaglandin E(2) (PGE(2)), a mediator of chronic inflammation and tumor progression, has emerged as a key molecule in MDSC biology. PGE(2) promotes MDSC development and their induction by additional factors, directly suppresses T cell immune responses and participates in the induction of other MDSC-associated suppressive factors, including Arg, iNOS and IDO. It further promotes MDSC recruitment to tumor environments through the local induction of CXCL12/SDF-1 and the induction and stabilization of the CXCL12 receptor, CXCR4, on tumor-associated MDSCs. The establishment of a positive feedback loop between PGE(2) and cyclooxygenase 2 (COX-2), the key regulator of PGE(2) synthesis, stabilizes the MDSC phenotype and is required for their suppressive function. The central role of PGE(2) in MDSC biology provides for a feasible target for counteracting MDSC-mediated immune suppression in cancer.
authors.affiliation: Department of Biotechnology, Jožef Stefan Institute, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Obermajer
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wong
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: Kirsten
authors.initials: K
authors.lastname: Moysich
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology*; D001120:Arginine / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology*; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D019718:Receptors, CXCR4; D001120:Arginine; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C574619:ARG1 protein, human; D001119:Arginase; D015232:Dinoprostone