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 language | English |
|---|---|
| Pages (from-to) | 2965-2974 |
| Number of pages | 10 |
| Journal | British Journal of Cancer |
| Volume | 110 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 10-06-2014 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
Cite this
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=84902551922&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902551922&partnerID=8YFLogxK
U2 - 10.1038/bjc.2014.251
DO - 10.1038/bjc.2014.251
M3 - Article
C2 - 24867687
AN - SCOPUS:84902551922
VL - 110
SP - 2965
EP - 2974
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 12
ER -