ABSTRACT
Dendritic cells (DC) have the potential to instigate a tumour-specific immune response, but their ability to prime naïve lymphocytes depends on their activation status. Thus, for tumour immunotherapy to be effective, the provision of appropriate DC activation stimuli such as Toll-like receptor (TLR) agonists is crucial in order to overcome immunosuppression associated with the tumour microenvironment. To address this, we investigated how ovarian carcinoma (OC)-associated ascites impedes activation of DC by TLR agonists. Our results show that ascites reduces the TLR-mediated up-regulation of CD86 and partially inhibits the production of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-12 and tumour necrosis factor α (TNFα) in monocyte-derived DC from healthy controls. We further observe an impaired T cell stimulatory capacity of DC upon activation with TLR agonists in the presence of ascites, indicating that their functionality is affected by the immunosuppressive factors. We identify IL-10 and prostaglandin E2 (PGE2) as the pivotal immunosuppressive components in OC-associated ascites compromising TLR-mediated DC activation. Interestingly, IL-10 is present in both ascites from patients with malignant OC and in peritoneal fluid from patients with benign ovarian conditions and both fluids have similar ability to reduce TLR-mediated DC activation. However, depletion of IL-10 from ascites revealed that the presence of paracrine IL-10 is not crucial for ascites-mediated suppression of DC activation in response to TLR activation. Unlike IL-10, PGE2 is absent from peritoneal fluid of patients with benign conditions and selectively reduces TNFα induction in response to TLR-mediated activation in the presence of OC-associated ascites. Our study highlights PGE2 as an immunosuppressive component of the malignant OC microenvironment rendering PGE2 a potentially important target for immunotherapy in OC.
Subject(s)
Dinoprostone/metabolism , Interleukin-10/metabolism , Ovarian Neoplasms/pathology , Toll-Like Receptors/metabolism , Antibodies, Neutralizing/metabolism , Ascites/metabolism , B7-2 Antigen/metabolism , Cells, Cultured , Dendritic Cells/cytology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dinoprostone/immunology , Female , Humans , Imidazoles/toxicity , Interleukin-10/immunology , Interleukin-12/analysis , Interleukin-12/metabolism , Interleukin-6/analysis , Interleukin-6/metabolism , Lipopolysaccharides/toxicity , Lymphocyte Activation/drug effects , Monocytes/cytology , Ovarian Neoplasms/immunology , Ovarian Neoplasms/metabolism , Poly I-C/toxicity , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Toll-Like Receptors/agonists , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/drug effectsABSTRACT
The aim of this study was to evaluate the safety, feasibility and cost-effectiveness of robotic assisted total hysterectomy and bilateral salpingo-oophorectomy (RATHBSO). Sixteen women underwent this new procedure for a variety of gynaecological indications. Outcome measures included operating time, estimated blood loss, length of hospital stay and cost. No intra-operative complications were recorded. Fifteen patients were discharged on day 1 following the procedure, and one patient stayed an extra day for pain relief. The cost of the procedure compared favourably with other surgical hysterectomy techniques. We conclude that RATHBSO is a feasible and safe surgical technique with all the advantages of minimal access surgery and equivalent cost.
