title: In Vivo Visualizing the IFN-β Response Required for Tumor Growth Control in a Therapeutic Model of Polyadenylic-Polyuridylic Acid Administration.
abstract: The crucial role that endogenously produced IFN-β plays in eliciting an immune response against cancer has recently started to be elucidated. Endogenous IFN-β has an important role in immune surveillance and control of tumor development. Accordingly, the role of TLR agonists as cancer therapeutic agents is being revisited via the strategy of intra/peritumoral injection with the idea of stimulating the production of endogenous type I IFN inside the tumor. Polyadenylic-polyuridylic acid (poly A:U) is a dsRNA mimetic explored empirically in cancer immunotherapy a long time ago with little knowledge regarding its mechanisms of action. In this work, we have in vivo visualized the IFN-β required for the antitumor immune response elicited in a therapeutic model of poly A:U administration. In this study, we have identified the role of host type I IFNs, cell populations that are sources of IFN-β in the tumor microenvironment, and other host requirements for tumor control in this model. One single peritumoral dose of poly A:U was sufficient to induce IFN-β, readily visualized in vivo. IFN-β production relied mainly on the activation of the transcription factor IFN regulatory factor 3 and the molecule UNC93B1, indicating that TLR3 is required for recognizing poly A:U. CD11c(+) cells were an important, but not the only source of IFN-β. Host type I IFN signaling was absolutely required for the reduced tumor growth, prolonged mice survival, and the strong antitumor-specific immune response elicited upon poly A:U administration. These findings add new perspectives to the use of IFN-β-inducing compounds in tumor therapy.
authors.affiliation: Department of Clinical Biochemistry, Faculty of Chemical Sciences, Center for Research in Clinical Biochemistry and Immunology, National University of Cordoba, X5000HUA Córdoba, Argentina;
authors.forename: David Andrés
authors.identifier: http://orcid.org/0000-0001-9581-1583
authors.initials: DA
authors.lastname: Nocera
authors.affiliation: Department of Clinical Biochemistry, Faculty of Chemical Sciences, Center for Research in Clinical Biochemistry and Immunology, National University of Cordoba, X5000HUA Córdoba, Argentina;
authors.forename: Emiliano
authors.initials: E
authors.lastname: Roselli
authors.affiliation: Department of Clinical Biochemistry, Faculty of Chemical Sciences, Center for Research in Clinical Biochemistry and Immunology, National University of Cordoba, X5000HUA Córdoba, Argentina;
authors.forename: Paula
authors.initials: P
authors.lastname: Araya
authors.affiliation: Department of Clinical Biochemistry, Faculty of Chemical Sciences, Center for Research in Clinical Biochemistry and Immunology, National University of Cordoba, X5000HUA Córdoba, Argentina; INSERM U932, Institut Curie, 75005 Paris, France;
authors.forename: Nicolás Gonzalo
authors.identifier: http://orcid.org/0000-0002-6386-8814
authors.initials: NG
authors.lastname: Nuñez
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Jadwiga
authors.identifier: http://orcid.org/0000-0003-1490-2542
authors.initials: J
authors.lastname: Jablonska
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Siegfried
authors.identifier: http://orcid.org/0000-0003-4790-3445
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Department of Clinical Biochemistry, Faculty of Chemical Sciences, Center for Research in Clinical Biochemistry and Immunology, National University of Cordoba, X5000HUA Córdoba, Argentina; Fundación para el Progreso de la Medicina. X5000EMS Córdoba, Argentina;
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gatti
authors.affiliation: Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Melanie M
authors.identifier: http://orcid.org/0000-0001-5431-6527
authors.initials: MM
authors.lastname: Brinkmann
authors.affiliation: Institute of Medical Microbiology, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany; and Research Group on Innate Immunity and Infection, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0002-3131-6580
authors.initials: A
authors.lastname: Kröger
authors.affiliation: Department of Clinical Biochemistry, Faculty of Chemical Sciences, Center for Research in Clinical Biochemistry and Immunology, National University of Cordoba, X5000HUA Córdoba, Argentina;
authors.forename: Gabriel
authors.initials: G
authors.lastname: Morón
authors.affiliation: Department of Clinical Biochemistry, Faculty of Chemical Sciences, Center for Research in Clinical Biochemistry and Immunology, National University of Cordoba, X5000HUA Córdoba, Argentina; mmaccioni@fcq.unc.edu.ar.
authors.forename: Mariana
authors.initials: M
authors.lastname: Maccioni
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D063646:Carcinogenesis; D006801:Humans; D007157:Immunologic Surveillance; D007167:Immunotherapy / Q000379:methods*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008546:Melanoma, Experimental; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D023421:Models, Animal; D009368:Neoplasm Transplantation; D011063:Poly A-U / Q000008:administration & dosage*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; D050838:Interferon Regulatory Factor-3; D026901:Membrane Transport Proteins; D051196:Toll-Like Receptor 3; C512254:UNC93B1 protein, mouse; D011063:Poly A-U; D016899:Interferon-beta