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

• Published in: British journal of cancer 2014-06, Vol.110 (12), p.2965-2974
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 631/250/516/1909; 631/67/1059/602; 631/67/1517/1709; 692/699/67/580; Adoptive Transfer; Animals; Arginase - blood; Benzamides - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Culture Media, Conditioned - pharmacology; Cyclohexanones - pharmacology; Dendritic Cells - immunology; Drug Resistance; Epidemiology; Female; Humans; Immune Tolerance; Interleukin-6 - biosynthesis; Interleukin-6 - blood; Interleukin-6 - immunology; Interleukin-8 - biosynthesis; Interleukin-8 - blood; Interleukin-8 - immunology; Macrophages - immunology; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Diagnostics; Molecular Medicine; Neoplasm Transplantation; Neoplasms, Glandular and Epithelial - immunology; Oncology; Ovarian Neoplasms - immunology; Signal Transduction - immunology; Transcription Factor RelA - antagonists & inhibitors; Transcription Factor RelA - genetics; Transcription Factor RelA - immunology; Transplantation, Heterologous
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.251

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- κ B 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- κ B inhibitor DHMEQ. Results: In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF- κ B 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- κ B inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells. Conclusions: NF- κ B is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF- κ B is an attractive target for EOC treatment.