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

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 PGE(2) 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 PGE(2) are differentially affected by PGE(2). Immature DC had a lower ability to migrate in the presence of PGE(2) compared to DC generated in vitro in the presence of PGE(2). Finally, we showed that PGE(2) induced a cytokine production profile and phenotypical features of tolerogenic DC, suggesting that the altered expression of PGE(2) enzymatic pathways may promote the cervical carcinogenesis by favouring (pre)cancer immunotolerance.