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

Hiroshi Nishio, Tomonori Yaguchi, J. Sugiyama, H. Sumimoto, K. Umezawa, Takashi Iwata, N. Susumu, T. Fujii, N. Kawamura, A. Kobayashi, J. Park, Daisuke Aoki, Yutaka Kawakami

研究成果: Article

35 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)2965-2974
ページ数10
ジャーナルBritish Journal of Cancer
110
発行部数12
DOI
出版物ステータスPublished - 2014 6 10

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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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

これを引用

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

:: British Journal of Cancer, 巻 110, 番号 12, 10.06.2014, p. 2965-2974.

研究成果: Article

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, 巻. 110, 番号 12, pp. 2965-2974. https://doi.org/10.1038/bjc.2014.251
Nishio, Hiroshi ; Yaguchi, Tomonori ; Sugiyama, J. ; Sumimoto, H. ; Umezawa, K. ; Iwata, Takashi ; Susumu, N. ; Fujii, T. ; Kawamura, N. ; Kobayashi, A. ; Park, J. ; Aoki, Daisuke ; Kawakami, Yutaka. / Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor. :: British Journal of Cancer. 2014 ; 巻 110, 番号 12. pp. 2965-2974.
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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.",
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author = "Hiroshi Nishio and Tomonori Yaguchi and J. Sugiyama and H. Sumimoto and K. Umezawa and Takashi Iwata and N. Susumu and T. Fujii and N. Kawamura and A. Kobayashi and J. Park and Daisuke Aoki and Yutaka Kawakami",
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T1 - Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor

AU - Nishio, Hiroshi

AU - Yaguchi, Tomonori

AU - Sugiyama, J.

AU - Sumimoto, H.

AU - Umezawa, K.

AU - Iwata, Takashi

AU - Susumu, N.

AU - Fujii, T.

AU - Kawamura, N.

AU - Kobayashi, A.

AU - Park, J.

AU - Aoki, Daisuke

AU - Kawakami, Yutaka

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.

KW - IL-6

KW - IL-8

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KW - Ovarian cancer

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