title: Stromal Fibroblasts Induce CCL20 through IL6/C/EBPβ to Support the Recruitment of Th17 Cells during Cervical Cancer Progression.
abstract: Cervical cancer is a consequence of persistent infection with human papillomaviruses (HPV). Progression to malignancy is linked to an inflammatory microenvironment comprising T-helper-17 (Th17) cells, a T-cell subset with protumorigenic properties. Neoplastic cells express only low endogenous levels of the Th17 chemoattractant CCL20, and therefore, it is unclear how Th17 cells are recruited to the cervical cancer tissue. In this study, we demonstrate that CCL20 was predominantly expressed in the stroma of cervical squamous cell carcinomas in situ. This correlated with stromal infiltration of CD4(+)/IL17(+) cells and with advancing International Federation of Gynecology and Obstetrics (FIGO) stage. Furthermore, we show that cervical cancer cells instructed primary cervical fibroblasts to produce high levels of CCL20 and to attract CD4/IL17/CCR6-positive cells, generated in vitro, in a CCL20/CCR6-dependent manner. Further mechanistic investigations identified cervical cancer cell-derived IL6 as an important mediator of paracrine CCL20 induction at the promoter, mRNA, and protein level in fibroblasts. CCL20 was upregulated through the recently described CCAAT/enhancer-binding protein β (C/EBPβ) pathway as shown with a dominant-negative version of C/EBPβ and through siRNA-mediated knockdown. In summary, our study defines a novel molecular mechanism by which cervical neoplastic cells shape their local microenvironment by instructing fibroblasts to support Th17 cell infiltration in a paracrine IL6/C/EBPβ-dependent manner. Th17 cells may in turn maintain chronic inflammation within high-grade cervical lesions to further promote cancer progression.
authors.affiliation: Institute of Virology and Center of Human and Molecular Biology, Medical Faculty, Saarland University, Homburg/Saar, Germany. barbara.walch@uks.eu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Walch-Rückheim
authors.affiliation: Department of Obstetrics and Gynecology, Saarland University, Homburg/Saar, Germany.
authors.forename: Russalina
authors.initials: R
authors.lastname: Mavrova
authors.affiliation: Institute of Virology and Center of Human and Molecular Biology, Medical Faculty, Saarland University, Homburg/Saar, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Henning
authors.affiliation: Institute of Virology and Center of Human and Molecular Biology, Medical Faculty, Saarland University, Homburg/Saar, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vicinus
authors.affiliation: Institute of Pathology, Saarland University, Homburg/Saar, Germany.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Institute of Pathology, Saarland University, Homburg/Saar, Germany.
authors.forename: Rainer Maria
authors.initials: RM
authors.lastname: Bohle
authors.affiliation: Department of Obstetrics and Gynecology, Saarland University, Homburg/Saar, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Juhasz-Böss
authors.affiliation: Department of Obstetrics and Gynecology, Saarland University, Homburg/Saar, Germany.
authors.forename: Erich-Franz
authors.initials: EF
authors.lastname: Solomayer
authors.affiliation: Institute of Virology and Center of Human and Molecular Biology, Medical Faculty, Saarland University, Homburg/Saar, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000276:immunology; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D014162:Transfection; D059016:Tumor Microenvironment / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000473:pathology*; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000473:pathology*
chemical_list: C108355:CCL20 protein, human; D002352:Carrier Proteins; D054418:Chemokine CCL20; C432687:EBNA1BP2 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins