title: Prevention of both direct and cross-priming of antitumor CD8+ T-cell responses following overproduction of prostaglandin E2 by tumor cells in vivo.
abstract: Defects in antitumor immune responses have been associated with increased release of prostaglandin E(2) (PGE(2)) as a result of overexpression of cyclooxygenase (COX)-2 by tumors. In this report, we examine the effects of PGE(2) on antitumor CD8(+) T-cell responses generated both by cross-presenting dendritic cells and by direct priming by tumor cells. Our data show that PGE(2) inhibits dendritic cell maturation, resulting in the abortive activation of naive CD8(+) T cells, and is dependent on interleukin-10 production by dendritic cells. Interaction of tumor cells with naïve CD8(+) T cells in the presence of PGE(2) in vitro results in the induction of CD8(+) CD28(-) T cells, which fail to proliferate or exhibit effector function. In vivo, overexpression of COX-2 by tumor cells results in a decrease in number of tumor-infiltrating dendritic cells and confers the ability of tumor cells to metastasize to the tumor draining lymph nodes.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ahmadi
authors.forename: David C
authors.initials: DC
authors.lastname: Emery
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgan
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009578:Nitrobenzenes / Q000494:pharmacology; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D053701:Receptors, Interleukin-10; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016753:Interleukin-10; D051546:Cyclooxygenase 2; D015232:Dinoprostone
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