title: Strict requirement for vector-induced type I interferon in efficacious antitumor responses to virally encoded IL12.
abstract: Host responses are increasingly considered important for the efficacious response to experimental cancer therapies that employ viral vectors, but little is known about the specific nature of host responses required. In this study, we investigated the role of host type I interferons (IFN-I) in the efficacy of virally delivered therapeutic genes. Specifically, we used a Semliki Forest virus encoding IL12 (SFV-IL12) based on its promise as an RNA viral vector for cancer treatment. Intratumoral injection of SFV-IL12 induced production of IFN-I as detected in serum. IFN-I production was abolished in mice deficient for the IFNβ transcriptional regulator IPS-1 and partially attenuated in mice deficient for the IFNβ signaling protein TRIF. Use of bone marrow chimeric hosts established that both hematopoietic and stromal cells were involved in IFN-I production. Macrophages, plasmacytoid, and conventional dendritic cells were each implicated based on cell depletion experiments. Further, mice deficient in the IFN-I receptor (IFNAR) abolished the therapeutic activity of SFV-IL12, as did a specific antibody-mediated blockade of IFNAR signaling. Reduced efficacy was not caused by an impairment in IL12 expression, because IFNAR-deficient mice expressed the viral IL12 transgene even more strongly than wild-type (WT) hosts. Chimeric host analysis for the IFNAR involvement established a strict requirement in hematopoietic cells. Notably, although tumor-specific CD8 T lymphocytes expanded robustly after intratumoral injection of WT mice with SFV-IL12, this did not occur in mice where IFNAR was inactivated genetically or pharmacologically. Overall, our results argued that the antitumor efficacy of a virally based transgene therapeutic relied strongly on a vector-induced IFN-I response, revealing an unexpected mechanism of action that is relevant to a broad array of current translational products in cancer research.
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain. imelero@unav.es mshervas@unav.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Jose I
authors.initials: JI
authors.lastname: Quetglas
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Clínica Universidad de Navarra, Pamplona, Navarra, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Reboredo
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Dubrot
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Rodriguez-Madoz
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Uxua
authors.initials: U
authors.lastname: Mancheño
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Erkuden
authors.initials: E
authors.lastname: Casales
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Jose I
authors.initials: JI
authors.lastname: Riezu-Boj
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Guillen
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ochoa
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Sanmamed
authors.affiliation: Centre National de la Recherche Scientifique (CNRS-UMR 8147), Université René Descartes Paris V, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thieblemont
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Smerdou
authors.affiliation: Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, University of Navarra, Navarra, Spain. imelero@unav.es mshervas@unav.es.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007167:Immunotherapy; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012367:RNA, Viral / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D019076:Transgenes
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D018664:Interleukin-12; D016899:Interferon-beta