Tumour‐derived prostaglandin E₂ and transforming growth factor‐β synergize to inhibit plasmacytoid dendritic cell‐derived interferon‐α

Abstract

SummaryIn previous studies we reported that plasmacytoid dendritic cells (PDC) infiltrating head and neck cancer tissue are functionally impaired, but the molecular basis for the functional deficiency remained unclear. Here we demonstrate that tumour-derived prostaglandin E2 (PGE 2 ) and transforming growth factor-b (TGF-b) increase interleukin-8 (IL-8) but synergistically inhibit interferon-a (IFN-a) and tumour necrosis factor (TNF) production of Toll-like receptor 7 (TLR7)-and Toll-like receptor 9 (TLR9)-stimulated PDC. The inhibitory effect of PGE 2 could be mimicked by the induction of cyclic AMP (cAMP) and by inhibitors of cyclooxygenase. The contribution of tumour-derived TGF-b was confirmed by the TGF-b antagonist SB-431542. Suppression of tumour-derived PGE 2 and TGF-b restored TLR-induced IFN-a production of PDC. Additionally, PGE 2 -and TGF-b-treated PDC display a 'tolerogenic' phenotype because of a downregulation of CD40 accompanied by an upregulation of CD86. Finally, in TLR-stimulated PDC, PGE 2 and TGF-b reduce the CCR7 : CXCR4 ratio, suggesting that PDC are impaired in their ability to migrate to tumour-draining lymph nodes but are retained in stromal cell-derived factor 1 (SDF-1)-expressing tissues. Based on these data, cyclooxygenase inhibitors and TGF-b antagonists may improve TLR7-and TLR9-based tumour immunotherapy.

Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer

“…The inhibitory role of TGF-b is consistent with a previous study showing that increased intratumoral IFN-a levels correlates with reduced TGF-b1 in breast cancer patients (33). Moreover, recent reports in mice and human showed that this cytokine contributes to peyer patches, splenic stromal, and tumor environments mediated inhibition of pDC capacity to produce IFN-a (29,34,35). The deleterious prognostic effect of TApDC in ovarian cancer could be related to the alteration of IFN-a production.…”

Monocyte-Mediated Inhibition of TLR9-Dependent IFN-α Induction in Plasmacytoid Dendritic Cells Questions Bacterial DNA as the Active Ingredient of Bacterial Lysates

“…Incubation of monocytes with the cyclooxygenase inhibitor indomethacin partially reduced the ability of monocyte-derived supernatants to inhibit PDC function, suggesting that in addition to IL-10, cyclooxygenasedependent formation of PGs contributes to inhibition of PDCs. Consistent with this finding, tumor-derived PGs were found to inhibit the ability of PDCs to produce IFN-a upon stimulation with CpG DNA (33).…”

Suppressive effect of aqueous humor on lipopolysaccharide-induced dendritic cell maturation

“…PGE 2, secreted mostly by the pigment epithelium, is widely recognized as an inflammatory molecule in the eye. At the same time, it is widely accepted that PGE 2 also helps to explain the immune escape of cancer by inhibiting maturation of the DC [14]. In this study, we first confirmed the immunosuppressive effects of TGF-b 2 on LPS-induced maturation of DC.…”