title: Differential Induction of Immunogenic Cell Death and Interferon Expression in Cancer Cells by Structured ssRNAs.
abstract: Activation of the RNA-sensing pattern recognition receptor (PRR) in cancer cells leads to cell death and cytokine expression. This cancer cell death releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce anti-tumor immunity. However, these cytokines and DAMPs also cause adverse inflammatory and thrombotic complications that can limit the overall therapeutic benefits of PRR-targeting anti-cancer therapies. To overcome this problem, we generated and evaluated two novel and distinct ssRNA molecules (immunogenic cell-killing RNA [ICR]2 and ICR4). ICR2 and ICR4 differentially stimulated cell death and PRR signaling pathways and induced different patterns of cytokine expression in cancer and innate immune cells. Interestingly, DAMPs released from ICR2- and ICR4-treated cancer cells had distinct patterns of stimulation of innate immune receptors and coagulation. Finally, ICR2 and ICR4 inhibited in vivo tumor growth as effectively as poly(I:C). ICR2 and ICR4 are potential therapeutic agents that differentially induce cell death, immune stimulation, and coagulation when introduced into tumors.
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710, USA; Duke Translational Research Institute, Duke University, Durham, NC 27710, USA. Electronic address: jaewoo.lee@duke.edu.
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710, USA; Duke Translational Research Institute, Duke University, Durham, NC 27710, USA.
authors.forename: Youngju
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710, USA; Duke Translational Research Institute, Duke University, Durham, NC 27710, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: White
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710, USA; Duke Translational Research Institute, Duke University, Durham, NC 27710, USA. Electronic address: bruce.sullenegr@duke.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Sullenger
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D064032:Calbindin 2 / Q000378:metabolism; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators; D007372:Interferons / Q000235:genetics*; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D021381:Protein Transport; D012313:RNA / Q000737:chemistry / Q000235:genetics*; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; C515070:CD300A protein, human; D064032:Calbindin 2; D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; D012313:RNA; D007372:Interferons
keywords: cell death; coagulation; inflammation; interferon; pattern recognition receptor