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Investigating the impact of ovarian carcinoma ascites on Toll-like receptor mediated dendritic cell activation

Student thesis: Doctoral ThesisDoctor of Philosophy

In this study, we investigate the impact of ovarian carcinoma associated ascites on dendritic cell (DC) activation by Toll-like receptor (TLR) agonists in vitro. DC have the potential to instigate a tumour-specific adaptive immune response, but their ability to induce differentiation of naïve lymphocytes into effector cells in lymphoid tissues is dependent on their activation status. Here, we examine whether DC activation by TLR agonists is impeded by ovarian carcinoma environment and if so, how these effects can be alleviated.
Our results show that ascites reduces the TLR-mediated up-regulation of the co-stimulatory molecule 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 donors. We further observe an impaired T cell stimulatory capacity of monocyte-derived DC upon activation with TLR agonists in the presence of ascites, indicating that their function as antigen-presenting cells is affected by the immunosuppressive factors. Selective neutralization of IL-10 and prostaglandin E2 (PGE2) in vitro alleviates the suppressive effects of ovarian carcinoma associated ascites. However, our results show that autocrine IL-10 contributes to the observed suppression. The role of autocrine PGE2 is yet unclear, as we have no indication that this protein is produced by TLR-activated monocyte-derived DC. We have established and present here an elegant method to dissect the relative contributions of ascites-derived versus autocrine IL-10 and PGE2, and experiments to this effect are ongoing.
The findings of this study can enhance the understanding of the ovarian carcinoma environment and its influence and relevance in the context of DC-based vaccines and other immunotherapeutic intervention strategies in ovarian carcinoma.
Original languageEnglish
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Award date2013

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