Abstract
IntroductionThe broccoli isothiocyanate sulforaphane was shown to inhibit inflammation and tumor progression, also in pancreatic cancer, while its effect on tumor immunity is poorly understood. We investigated the immunoregulatory effect of sulforaphane on human dendritic cells alone and in presence of pancreatic tumor antigens, as well as underlying molecular mechanisms.MethodsSulforaphane-treated human dendritic cells were matured in vitro with a cytokine cocktail, and the expression of regulatory molecules was examined by flow cytometry. The subsequent T-cell response was analyzed by T-cell proliferation assay and CD25 expression. To confirm the findings, dendritic cells pulsed with pancreatic cancer-derived tumor antigens were used. To identify the involved pathway- and microRNA-signaling in sulforaphane-treated dendritic cells, inhibitors of various signaling pathways, western blot analysis, microRNA array, and bioinformatic analysis were applied.ResultsSulforaphane modulated the expression of the costimulatory CD80, CD83 and the suppressive B7-H1 molecules on dendritic cells and thereby promoted activation of T cells. The effect was verified in presence of pancreatic tumor antigens. Phosphorylation of STAT3 in dendritic cells was diminished by sulforaphane, and the inhibition of JAK/STAT3 led to downregulation of B7-H1 expression. Among the identified top 100 significant microRNA candidates, the inhibition of miR-155-5p, important for the expression of costimulatory molecules, and the induction of miR-194-5p, targeting the B7-H1 gene, were induced by sulforaphane.ConclusionOur findings demonstrate that sulforaphane promotes T-cell activation by dendritic cells through the modulation of regulatory molecules, JAK/STAT3- and microRNA-signaling in healthy conditions and in context of pancreatic cancer-derived antigens. They explore the immunoregulatory properties of sulforaphane and justify further research on nutritional strategies in the co-treatment of cancer.
Highlights
The broccoli isothiocyanate sulforaphane was shown to inhibit inflammation and tumor progression, in pancreatic cancer, while its effect on tumor immunity is poorly understood
We examined the effect of sulforaphane on the expression of dendritic cells (DCs) regulatory molecules and on the consequent activation capacity of DCs towards T cells in normal conditions and in context of pancreatic cancer cellderived antigens
Monocyte-derived dendritic cells (MoDCs) were treated with sulforaphane from 5 to 50 μM because these concentrations are in the range of observed antitumor effects in established Pancreatic ductal adenocarcinoma (PDA) cell lines [6]
Summary
The broccoli isothiocyanate sulforaphane was shown to inhibit inflammation and tumor progression, in pancreatic cancer, while its effect on tumor immunity is poorly understood. Sulforaphane, a natural isothiocyanate present abundantly in cruciferous vegetables, such as broccoli, attracted considerable attention in oncology first because of epidemiological studies. They demonstrated that diets rich in sulforaphane-containing vegetables of the Brassicaceae family can lower the incidences of various cancer types, including pancreatic cancer [1]. A phase II clinical trial with 20 patients suffering from recurrent prostate cancer suggested a suppressive effect of sulforaphane-rich broccoli sprout extract on the expression of the prostate-specific tumor progression marker PSA [9]. Data of our recent prospective pilot study conducted with 40 patients with advanced non-resectable PDA point to a survival advantage after consuming sulforaphane-rich broccoli sprout powder [11]
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