Targeted activation of RNA helicase retinoic acid-inducible gene-I induces proimmunogenic apoptosis of human ovarian cancer cells.
Most malignant cells are poorly immunogenic and fail to elicit an effective antitumor immune response. In contrast, viral infections of cells are promptly detected and eliminated by the immune system. Viral recognition critically hinges on cytosolic nucleic acid receptors that include the proinflammatory RNA helicase retinoic acid-inducible gene-I (RIG-I). Here, we show that targeted delivery of RIG-I agonists induced ovarian cancer cells to upregulate HLA class I and to secrete the proinflammatory cytokines CXCL10, CCL5, interleukin-6, tumor necrosis factor-alpha, and IFN-beta. Ovarian cancer cells stimulated via RIG-I became apoptotic and were readily phagocytosed by monocytes and monocyte-derived dendritic cells, which in turn upregulated HLA class I/II and costimulatory molecules and released CXCL10 and IFN-alpha. Our findings offer proof of principle that mimicking viral infection in ovarian cancer cells triggers an immunogenic form of tumor cell apoptosis that may enhance immunotherapy of ovarian cancer.
Kübler
Kirsten
K
Institute of Clinical Chemistry and Pharmacology, Center for Integrated Oncology, University of Bonn, Bonn, Germany.
Gehrke
Nadine
N
Riemann
Soheila
S
Böhnert
Volker
V
Zillinger
Thomas
T
Hartmann
Evelyn
E
Pölcher
Martin
M
Rudlowski
Christian
C
Kuhn
Walther
W
Hartmann
Gunther
G
Barchet
Winfried
W
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001201:Ascites / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D004789:Enzyme Activation; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D008024:Ligands; D009000:Monocytes / Q000276:immunology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D011067:Poly dA-dT / Q000008:administration & dosage; D012330:RNA, Double-Stranded / Q000008:administration & dosage; D011971:Receptors, Immunologic
D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D011067:Poly dA-dT; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases