Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor

H. Nishio, T. Yaguchi, J. Sugiyama, H. Sumimoto, K. Umezawa, T. Iwata, N. Susumu, Takuma Fujii, N. Kawamura, A. Kobayashi, J. Park, D. Aoki, Y. Kawakami

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2965-2974
Number of pages10
JournalBritish Journal of Cancer
Volume110
Issue number12
DOIs
Publication statusPublished - 10-06-2014
Externally publishedYes

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Ovarian Neoplasms
Immunosuppression
Interleukin-8
Arginase
Interleukin-6
Immunosuppressive Agents
T-Lymphocytes
Nude Mice
Macrophages
Ovarian epithelial cancer
Immunity
Neoplasms
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Nishio, H. ; Yaguchi, T. ; Sugiyama, J. ; Sumimoto, H. ; Umezawa, K. ; Iwata, T. ; Susumu, N. ; Fujii, Takuma ; Kawamura, N. ; Kobayashi, A. ; Park, J. ; Aoki, D. ; Kawakami, Y. / Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor. In: British Journal of Cancer. 2014 ; Vol. 110, No. 12. pp. 2965-2974.
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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.",
author = "H. Nishio and T. Yaguchi and J. Sugiyama and H. Sumimoto and K. Umezawa and T. Iwata and N. Susumu and Takuma Fujii and N. Kawamura and A. Kobayashi and J. Park and D. Aoki and Y. Kawakami",
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Nishio, H, Yaguchi, T, Sugiyama, J, Sumimoto, H, Umezawa, K, Iwata, T, Susumu, N, Fujii, T, Kawamura, N, Kobayashi, A, Park, J, Aoki, D & Kawakami, Y 2014, 'Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor', British Journal of Cancer, vol. 110, no. 12, pp. 2965-2974. https://doi.org/10.1038/bjc.2014.251

Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor. / Nishio, H.; Yaguchi, T.; Sugiyama, J.; Sumimoto, H.; Umezawa, K.; Iwata, T.; Susumu, N.; Fujii, Takuma; Kawamura, N.; Kobayashi, A.; Park, J.; Aoki, D.; Kawakami, Y.

In: British Journal of Cancer, Vol. 110, No. 12, 10.06.2014, p. 2965-2974.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor

AU - Nishio, H.

AU - Yaguchi, T.

AU - Sugiyama, J.

AU - Sumimoto, H.

AU - Umezawa, K.

AU - Iwata, T.

AU - Susumu, N.

AU - Fujii, Takuma

AU - Kawamura, N.

AU - Kobayashi, A.

AU - Park, J.

AU - Aoki, D.

AU - Kawakami, Y.

PY - 2014/6/10

Y1 - 2014/6/10

N2 - 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.

AB - 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.

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