title: Immunogenic cell death of human ovarian cancer cells induced by cytosolic poly(I:C) leads to myeloid cell maturation and activates NK cells.
abstract: Owing to high rates of tumor relapse, ovarian cancer remains a fatal disease for which new therapeutic approaches are urgently needed. Accumulating evidence indicates that immune stimulation may delay or even prevent disease recurrence in ovarian cancer. In order to elicit proinflammatory signals that induce or amplify antitumor immune reactivity, we mimicked viral infection in ascites-derived ovarian cancer cells. By transfection or electroporation we targeted the synthetic double-stranded RNA poly(I:C) intracellularly in order to activate melanoma differentiation-associated gene-5 (MDA-5), a sensor of viral RNA in the cytosol of somatic cells. Cancer cells reacted with enhanced expression of HLA-class I, release of CXCL10, IL-6, and type I IFN as well as tumor cell apoptosis. Monocytes and monocyte-derived DCs (MoDCs) engulfed MDA-5-activated cancer cells, and subsequently upregulated HLA-class I/II and costimulatory molecules, and secreted CXCL10 and IFN-α. Further, this proinflammatory milieu promoted cytolytic activity and IFN-γ secretion of NK cells. Thus, our data suggest that the engagement of MDA-5 in a whole tumor cell vaccine is a promising approach for the immunotherapy of ovarian cancer.
authors: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors: Kirsten
authors: K
authors: Kübler
authors: Carola
authors: C
authors: tho Pesch
authors: Nadine
authors: N
authors: Gehrke
authors: Soheila
authors: S
authors: Riemann
authors: Juliane
authors: J
authors: Dassler
authors: Christoph
authors: C
authors: Coch
authors: Jennifer
authors: J
authors: Landsberg
authors: Vera
authors: V
authors: Wimmenauer
authors: Martin
authors: M
authors: Pölcher
authors: Christian
authors: C
authors: Rudlowski
authors: Thomas
authors: T
authors: Tüting
authors: Walther
authors: W
authors: Kuhn
authors: Gunther
authors: G
authors: Hartmann
authors: Winfried
authors: W
authors: Barchet
mesh_terms: D000818:Animals; D017209:Apoptosis; D001201:Ascites; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018274:Electroporation; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology*; D014162:Transfection
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; D016898:Interferon-alpha; D015850:Interleukin-6; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C