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In the present study, we postulate that molecules secreted by (pre)neoplastic epithelial cells of the genital tract (cervix\/vulva) might attract pDCs but also modify their proper functionality, allowing these cells to initiate a tolerogenic response interfering with antitumor immunity. We demonstrated that pDCs are recruited during the cervical metaplasia\u2010dysplasia\u2010cancer sequence, through the action of their chemoattractant, chemerin. We showed that stimulated\u2010pDCs exposed to cervical\/vulvar tumor microenvironment display an altered phenotype. We also demonstrated that cervical\/vulvar neoplastic keratinocytes inhibit the proper function of pDCs by decreasing their IFN\u03b1 secretion in response to CpG oligonucleotides. In parallel, we observed that (pre)neoplastic areas of the cervix are infiltrated by FoxP3<jats:sup>+<\/jats:sup> Treg cells which colocalize with pDCs. Accordingly, pDCs cocultured with cervical\/vulvar neoplastic keratinocytes have the capacity to induce a Treg cell differentiation from na\u00efve CD4<jats:sup>+<\/jats:sup> T cells, which is in agreement with the development of a tolerogenic response. We identified HMGB1 as a soluble factor produced by neoplastic keratinocytes from the genital tract involved in pDCs functional alteration. Indeed, this molecule inhibited pDC maturation, decreased IFN\u03b1 secretion following TLR9 stimulation and forced these cells to become tolerogenic. In contrast, inhibition of HMGB1 restored pDC phenotype. Our findings indicate that the use of inhibitory molecules notably directed against HMGB1 in cervical\/vulvar (pre)neoplastic lesions might prevent alterations of pDCs functionality and represent an attractive therapeutic strategy to overcome immune tolerance in cancers.<\/jats:p>","DOI":"10.1002\/ijc.29389","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T18:48:29Z","timestamp":1418150909000},"page":"345-358","source":"Crossref","is-referenced-by-count":41,"title":["HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells"],"prefix":"10.1002","volume":"137","author":[{"given":"St\u00e9phanie","family":"Demoulin","sequence":"first","affiliation":[{"name":"Department of Pathology, Laboratory of Experimental Pathology University of Li\u00e8ge, GIGA\u2010Cancer 4000 Li\u00e8ge 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