Interleukin-10 and prostaglandin E2 have complementary but distinct suppressive effects on Toll-like receptor-mediated dendritic cell activation in ovarian carcinoma

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.

Comparative analysis of abdominal fluid cytokine levels in ovarian hyperstimulation syndrome (OHSS)

“…Moreover, the levels were highest in the ascites of the OC patients. This finding is consistent with other recently published data [7] and with an angiogenetic role for IL-8 in malignancy [28] and a pivotal immunosuppressive role for IL-10 in OCassociated ascites when activation of dendritic cells via toll-like receptors is compromised [29].…”

Role of the body mass index in the genesis of ascites in ovarian cancer: a forensic case and review of the literature

“…The role of ascites and its microenvironment, in the evolution and prognosis of ovarian carcinoma, can be related to the levels of immunosuppressive cytokines such as interleukin (IL) 10, and the suppression of CD86, IL-6 and IL-12p40 as response to activation of toll-like receptors (TLRs). There is no correlation between Tumor Necrosis Factor (TNF)-alpha and IL-10 13. In one study, a group of patients, characterised by upregulation of gene expression of IFN-gamma, showed a longer survival.…”

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

“…IL-10 and PGE2 induce overlapping yet distinct inhibitory effects on Mφs (Brencicova et al, 2017). Further studies are required to decipher the relative anti-inflammatory functions of IL-10 and PGE2 in the intestine.…”