title: HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells.
abstract: Acquisition of an impaired functionality by plasmacytoid dendritic cells (pDCs) contributing to cancer progression has been documented in different types of cancers. 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-dysplasia-cancer sequence, through the action of their chemoattractant, chemerin. We showed that stimulated-pDCs 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 IFNα secretion in response to CpG oligonucleotides. In parallel, we observed that (pre)neoplastic areas of the cervix are infiltrated by FoxP3(+) Treg cells which colocalize with pDCs. Accordingly, pDCs cocultured with cervical/vulvar neoplastic keratinocytes have the capacity to induce a Treg cell differentiation from naïve CD4(+) 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 IFNα 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.
authors.affiliation: Department of Pathology, Laboratory of Experimental Pathology, University of Liège, GIGA-Cancer, 4000, Liège, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Demoulin
authors.affiliation: Department of Pathology, Laboratory of Experimental Pathology, University of Liège, GIGA-Cancer, 4000, Liège, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Herfs
authors.affiliation: Department of Pathology, University Hospital of Liège, 4000, Liège, Belgium.
authors.forename: Joan
authors.initials: J
authors.lastname: Somja
authors.affiliation: Department of Pathology, Laboratory of Experimental Pathology, University of Liège, GIGA-Cancer, 4000, Liège, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roncarati
authors.affiliation: Department of Pathology, University Hospital of Liège, 4000, Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Department of Pathology, Laboratory of Experimental Pathology, University of Liège, GIGA-Cancer, 4000, Liège, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hubert
mesh_terms: D063646:Carcinogenesis / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002584:Cervix Uteri / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D018925:Chemokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016898:Interferon-alpha; C478630:RARRES2 protein, human; D051217:Toll-Like Receptor 9
keywords: HMGB1; Treg cells; cervical cancers; plasmacytoid dendritic cells; tolerogenicity