title: RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis, IL-1α release, and efficient paracrine dendritic cell activation.
abstract: Previous studies have shown that cervical cancer cells only release low levels of pro-inflammatory cytokines owing to infection with human papillomaviruses. This results in low immunogenicity of the cancer cells. The viral dsRNA analog PolyIC has been suggested as a promising adjuvant for cervical cancer immunotherapy. However, little is known about the molecular requirements resulting in successful immune activation. Here, we demonstrate that stimulation of cervical cancer cells with PolyIC induced necroptotic cell death, which was strictly dependent on the expression of the receptor-interacting protein kinase RIPK3. Necroptotic cancer cells released interleukin-1α (IL-1α), which was required for powerful activation of dendritic cells (DC) to produce IL-12, a cytokine critical for anti-tumor responses. Again both, IL-1α release and DC activation, were strictly dependent on RIPK3 expression in the tumor cells. Of note, our in situ analyses revealed heterogeneous RIPK3 expression patterns in cervical squamous cell carcinomas and adenocarcinomas. In summary, our study identified a novel RIPK3-dependent mechanism that explains how PolyIC-treatment of cervical cancer cells leads to potent DC activation. Our findings suggest that the RIPK3 expression status in cervical cancer cells might critically influence the outcome of PolyIC-based immunotherapeutic approaches and should therefore be assessed prior to immunotherapy.
authors.affiliation: Center for Molecular Medicine Cologne and Institute of Virology, University of Cologne, Germany.
authors.forename: Susanne V
authors.initials: SV
authors.lastname: Schmidt
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Seibert
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Walch-Rückheim
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vicinus
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Kamionka
authors.affiliation: Center for Molecular Medicine Cologne and Institute of Virology, University of Cologne, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pahne-Zeppenfeld
authors.affiliation: Department of Gynecology and Obstetrics, Saarland University, Homburg/Saar, Germany.
authors.forename: Erich-Franz
authors.initials: EF
authors.lastname: Solomayer
authors.affiliation: Department of Pathology, Saarland University, Homburg/Saar, Germany.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Saarland University, Homburg/Saar, Germany.
authors.forename: Rainer M
authors.initials: RM
authors.lastname: Bohle
authors.affiliation: Center for Molecular Medicine Cologne and Institute of Virology, University of Cologne, Germany.|Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D053148:Caspase 3 / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D053582:Interleukin-1alpha / Q000378:metabolism*; D009336:Necrosis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D027383:Papillomaviridae / Q000187:drug effects; D030361:Papillomavirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D019899:Paracrine Communication / Q000187:drug effects*; D011070:Poly I-C / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000473:pathology*
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D007369:Interferon Inducers; D053582:Interleukin-1alpha; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D018664:Interleukin-12; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D011070:Poly I-C
keywords: RIPK3; cervical cancer; dendritic cells; human papilloma virus