title: Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer.
abstract: Cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 underlie an immunosuppressive network that is important in the pathogenesis of non-small cell lung cancer. CD4+ CD25+ T regulatory (Treg) cells play an important role in maintenance of immunologic self-tolerance. CD4+ CD25+ Treg cell activities increase in lung cancer and appear to play a role in suppressing antitumor immune responses. Definition of the pathways controlling Treg cell activities will enhance our understanding of limitation of the host antitumor immune responses. Tumor-derived COX-2/PGE2 induced expression of the Treg cell-specific transcription factor, Foxp3, and increased Treg cell activity. Assessment of E-prostanoid (EP) receptor requirements revealed that PGE2-mediated induction of Treg cell Foxp3 gene expression was significantly reduced in the absence of the EP4 receptor and ablated in the absence of the EP2 receptor expression. In vivo, COX-2 inhibition reduced Treg cell frequency and activity, attenuated Foxp3 expression in tumor-infiltrating lymphocytes, and decreased tumor burden. Transfer of Treg cells or administration of PGE2 to mice receiving COX-2 inhibitors reversed these effects. We conclude that inhibition of COX-2/PGE2 suppresses Treg cell activity and enhances antitumor responses.
authors.affiliation: Department of Medicine, Lung Cancer Research Program, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1960, USA.
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
authors.forename: Seok-Chul
authors.initials: SC
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Karen
authors.initials: K
authors.lastname: Reckamp
authors.forename: Brian
authors.initials: B
authors.lastname: Gardner
authors.forename: Felicita
authors.initials: F
authors.lastname: Baratelli
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Raj K
authors.initials: RK
authors.lastname: Batra
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D018078:Receptors, Prostaglandin E / Q000819:agonists; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014162:Transfection
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D015375:Receptors, Interleukin-2; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone