title: Induction of interferon pathways mediates in vivo resistance to oncolytic adenovirus.
abstract: Oncolytic adenoviruses are an emerging experimental approach for treatment of tumors refractory to available modalities. Although preclinical results have been promising, and clinical safety has been excellent, it is also apparent that tumors can become virus resistant. The resistance mechanisms acquired by advanced tumors against conventional therapies are increasingly well understood, which has allowed development of countermeasures. To study this in the context of oncolytic adenovirus, we developed two in vivo models of acquired resistance, where initially sensitive tumors eventually gain resistance and relapse. These models were used to investigate the phenomenon on RNA and protein levels using two types of analysis of microarray data, quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Interferon (IFN) signaling pathways were found upregulated and Myxovirus resistance protein A (MxA) expression was identified as a marker correlating with resistance, while transplantation experiments suggested a role for tumor stroma in maintaining resistance. Furthermore, pathway analysis suggested potential therapeutic targets in oncolytic adenovirus-resistant cells. Improved understanding of the antiviral phenotype causing tumor recurrence is of key importance in order to improve treatment of advanced tumors with oncolytic adenoviruses. Given the similarities between mechanisms of action, this finding might be relevant for other oncolytic viruses as well.
authors.affiliation: Cancer Gene Therapy Group, Molecular Cancer Biology Program, Transplantation Laboratory, Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Liikanen
authors.forename: Vladia
authors.initials: V
authors.lastname: Monsurrò
authors.forename: Laura
authors.initials: L
authors.lastname: Ahtiainen
authors.forename: Mari
authors.initials: M
authors.lastname: Raki
authors.forename: Tanja
authors.initials: T
authors.lastname: Hakkarainen
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.forename: Sophie
authors.initials: S
authors.lastname: Escutenaire
authors.forename: Otto
authors.initials: O
authors.lastname: Hemminki
authors.forename: João D
authors.initials: JD
authors.lastname: Dias
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.forename: Daniela
authors.initials: D
authors.lastname: Marzioni
authors.forename: Marco
authors.initials: M
authors.lastname: Colombatti
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007372:Interferons / Q000096:biosynthesis*; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D050130:Oncolytic Virotherapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D017931:DNA Primers; D007372:Interferons