HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells

• Published in: International journal of cancer Vol. 137; no. 2; pp. 345 - 358
• Main Authors: Demoulin, Stéphanie, Herfs, Michael, Somja, Joan, Roncarati, Patrick, Delvenne, Philippe, Hubert, Pascale
• Format: Journal Article Web Resource
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.07.2015; Wiley Liss, Inc
• Subjects: Cancer; Carcinogenesis - immunology; Carcinogenesis - pathology; Cell Differentiation - immunology; Cell Line, Tumor; Cells; Cervical cancer; cervical cancers; Cervix Uteri - immunology; Cervix Uteri - metabolism; Cervix Uteri - pathology; Chemokines - immunology; Chemokines - metabolism; Coculture Techniques; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; HMGB1; HMGB1 Protein - immunology; HMGB1 Protein - metabolism; Human health sciences; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Interferon-alpha - immunology; Interferon-alpha - metabolism; Keratinocytes - immunology; Keratinocytes - metabolism; Keratinocytes - pathology; Medical research; Microscopy, Confocal; Oncologie; Oncology; plasmacytoid dendritic cells; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sciences de la santé humaine; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; tolerogenicity; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology; Toll-Like Receptor 9 - metabolism; Treg cells; Tumor Microenvironment - immunology; Tumorigenesis; tolerogenicity; Treg cells; plasmacytoid dendritic cells; cervical cancers; HMGB1
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.29389

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. What's new? The human immune system usually strikes with deadly efficiency. Somehow, though, tumors evade destruction, despite the presence of distinctive tumor antigens. In fact, tumors actively train the immune cells to tolerate their antigens, using plasmacytoid dendritic cells (pDCs). In this paper, the authors asked whether cervical cells send out a molecular signal that summons the pDCs and enlists them in the service of the tumor. They discovered that the protein HMGB1, produced by tumor cells, interfered with pDCs' maturation and created an immune tolerance toward the tumor. Inhibiting HMGB1 restored normal pDC function, suggesting a possible treatment angle.