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-α, and IFN-β. 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-α. 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. Cancer Res; 70(13); 5293-304. ©2010 AACR.

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 HLAclass 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-a. Further, this proinflammatory milieu promoted cytolytic activity and IFN-c 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.

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Supplementary Figure 1 from Targeted Activation of RNA Helicase Retinoic Acid–Inducible Gene-I Induces Proimmunogenic Apoptosis of Human Ovarian Cancer Cells

Supplementary Methods, Tables 1-4, Figure Legends 1-9 from Targeted Activation of RNA Helicase Retinoic Acid–Inducible Gene-I Induces Proimmunogenic Apoptosis of Human Ovarian Cancer Cells

Supplementary Figures 2-3 from Targeted Activation of RNA Helicase Retinoic Acid–Inducible Gene-I Induces Proimmunogenic Apoptosis of Human Ovarian Cancer Cells

Supplementary Figures 4-7 from Targeted Activation of RNA Helicase Retinoic Acid–Inducible Gene-I Induces Proimmunogenic Apoptosis of Human Ovarian Cancer Cells

Supplementary Figures 8-9 from Targeted Activation of RNA Helicase Retinoic Acid–Inducible Gene-I Induces Proimmunogenic Apoptosis of Human Ovarian Cancer Cells