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Defensins induce the recruitment of dendritic cells in cervical human papillomavirus-associated (pre)neoplastic lesions formed in vitro and transplanted in vivo

Pascale Hubert^*,1, Ludivine Herman^*, Catherine Maillard, Jean-Hubert Caberg^*, Arjen Nikkels, Gerald Pierard, Jean-Marie Foidart, Agnès Noel, Jacques Boniver^* and Philippe Delvenne^*

^* Department of Pathology,

Laboratory of Tumor and Development Biology,

Department of Dermatopathology, University Hospital of Liège, CHU Sart Tilman, Liège, Belgium

¹Correspondence: Department of Pathology B35, University of Liège, Sart Tilman, 4000 Liège, Belgium, E-mail: P.hubert{at}ulg.ac.be

In addition to their direct antimicrobial activity, defensins might also influence adaptive immunity by attracting immature dendritic cells (DC). As these cells have been shown to be deficient in uterine cervix carcinogenesis, we evaluated the ability of -defensin (HNP-2, human neutrophil defensin 2) and ß-defensin (HßD2, human beta defensin 2) to stimulate their migration in human papillomavirus (HPV)-associated (pre)cancers. We first observed, using RT-PCR and immunohistology, that HßD2 is absent in HPV-transformed keratinocytes and that it is weakly expressed in cervical (pre)neoplastic lesions in comparison with normal keratinocytes. We next demonstrated that defensins exert a chemotactic activity for DC in a Boyden Chamber assay and stimulate their infiltration in an in vitro-formed (pre)neoplastic epithelium (organotypic culture of HPV-transformed keratinocytes). To evaluate the ability of defensins also to recruit DC in vivo, we developed a model of immunodeficient mice grafted with organotypic cultures of HPV⁺ keratinocytes, which form an epithelium similar to a high-grade neoplastic lesion, with tumoral invasion and neovascularization. Intravenously injected human DC were able to infiltrate grafts of HPV⁺ keratinocytes after administration of HNP-2 in the transplantation chamber. Taken together, these results suggest that defensins could reverse a frequent immune alteration observed in cancer development.—Hubert, P., Herman, L., Maillard, C., Caberg, J-H., Nikkels, A., Pierard, G., Foidart, J-M., Noel, A., Boniver, J., Delvenne, P. Defensins induce the recruitment of dendritic cells in cervical human papillomavirus-associated (pre)neoplastic lesions formed in vitro and transplanted in vivo.

Key Words: alpha and beta defensins • antigen presenting cells • HPV • cervical lesions • migration