RRC ID 68787
Author 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.
Title Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor.
Journal Br J Cancer
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.
Volume 110(12)
Pages 2965-74
Published 2014-6-10
DOI 10.1038/bjc.2014.251
PII bjc2014251
PMID 24867687
PMC PMC4056060
MeSH Adoptive Transfer Animals Arginase / blood Benzamides / pharmacology Carcinoma, Ovarian Epithelial Cell Line, Tumor Culture Media, Conditioned / pharmacology Cyclohexanones / pharmacology Dendritic Cells / immunology 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 Neoplasm Transplantation Neoplasms, Glandular and Epithelial / immunology* Ovarian Neoplasms / immunology* Signal Transduction / immunology Transcription Factor RelA / antagonists & inhibitors Transcription Factor RelA / genetics Transcription Factor RelA / immunology* Transplantation, Heterologous
IF 5.791
Human and Animal Cells JHOS-2(RCB1521)