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High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells

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Abstract

Although human papillomavirus (HPV) DNA is detected in the majority of squamous intraepithelial lesions (SIL) and carcinoma (SCC) of the uterine cervix, the persistence or progression of cervical lesions suggest that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most SIL show quantitative and functional alterations of Langerhans cells (LC). The aim of this study was to determine whether prostaglandins (PG) may affect LC density in the cervical (pre)neoplastic epithelium. We first demonstrated that the epithelial expression of PGE2 enzymatic pathways, including cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1), is higher in SIL and SCC compared to the normal exocervical epithelium and inversely correlated to the density of CD1a-positive LC. By using cell migration assays, we next showed that the motility of immature dendritic cells (DC) and DC partially differentiated in vitro in the presence of PGE2 are differentially affected by PGE2. Immature DC had a lower ability to migrate in the presence of PGE2 compared to DC generated in vitro in the presence of PGE2. Finally, we showed that PGE2 induced a cytokine production profile and phenotypical features of tolerogenic DC, suggesting that the altered expression of PGE2 enzymatic pathways may promote the cervical carcinogenesis by favouring (pre)cancer immunotolerance.

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Acknowledgments

This work was supported by the Marshall Programme of the Walloon Region (Neoangio No 616476), the Belgian Fund for Medical Scientific Research and the Centre Anti-Cancereux près l’Université de Liège. P. Delvenne and M. Herfs are Research Associates of the Belgian National Fund for Scientific Research.

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Correspondence to Philippe Delvenne.

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M. Herfs and L. Herman contributed equally to this work.

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Herfs, M., Herman, L., Hubert, P. et al. High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells. Cancer Immunol Immunother 58, 603–614 (2009). https://doi.org/10.1007/s00262-008-0584-4

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