title: Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor.
abstract: BACKGROUND
  Although T-cell immunity is thought to be involved in the prognosis of epithelial ovarian cancer (EOC) patients, immunosuppressive conditions hamper antitumour immune responses. Thus, their mechanisms and overcoming strategies need to be investigated.
  
  
  METHODS
  The role of NF-κB in human EOC cells and macrophages was evaluated by in vitro production of immunosuppressive IL-6 and IL-8 by EOC cells and in vivo analysis of immune responses in nude mice implanted with human EOC cells using an NF-κB inhibitor DHMEQ.
  
  
  RESULTS
  In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF-κB inhibitor DHMEQ inhibited the production of IL-6 and IL-8 by EOC cell lines. Immunosuppression of human DCs and macrophages by culture supernatant of EOC cells was reversed with the pretreatment of DHMEQ. Administration of DHMEQ to nude mice implanted with human EOC resulted in the restoration of T-cell stimulatory activity of murine DCs along with the reduction of tumour accumulation and arginase expression of MDSCs. Nuclear factor-κB inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells.
  
  
  CONCLUSIONS
  NF-κB is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF-κB is an attractive target for EOC treatment.
authors.affiliation: 1] Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan [2] Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nishio
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yaguchi
authors.affiliation: 1] Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan [2] Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Sugiyama
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sumimoto
authors.affiliation: Department of Applied Chemistry, Keio University Faculty of Science and Technology, Yokohama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Umezawa
authors.affiliation: 1] Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan [2] Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Iwata
authors.affiliation: Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Susumu
authors.affiliation: Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kawamura
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Aoki
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical and Science Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001119:Arginase / Q000097:blood; D001549:Benzamides / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003512:Cyclohexanones / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D014183:Transplantation, Heterologous
chemical_list: D001549:Benzamides; C508606:CXCL8 protein, human; D017077:Culture Media, Conditioned; D003512:Cyclohexanones; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D051996:Transcription Factor RelA; C464444:dehydroxymethylepoxyquinomicin; D001119:Arginase