title: Resistance to oncolytic myxoma virus therapy in nf1(-/-)/trp53(-/-) syngeneic mouse glioma models is independent of anti-viral type-I interferon.
abstract: Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results in clinical evaluations. Of concern are the low levels of tumour infection and viral replication within the tumour. This discrepancy between the laboratory and the clinic could result from the disparity of xenograft versus syngeneic models in determining in vivo viral infection, replication and treatment efficacy. Here we describe a panel of primary mouse glioma lines derived from Nf1 (+/-) Trp53 (+/-) mice in the C57Bl/6J background for use in the preclinical testing of the oncolytic virus Myxoma (MYXV). These lines show a range of susceptibility to MYXV replication in vitro, but all succumb to viral-mediated cell death. Two of these lines orthotopically grafted produced aggressive gliomas. Intracranial injection of MYXV failed to result in sustained viral replication or treatment efficacy, with minimal tumour infection that was completely resolved by 7 days post-infection. We hypothesized that the stromal production of Type-I interferons (IFNα/β) could explain the resistance seen in these models; however, we found that neither the cell lines in vitro nor the tumours in vivo produce any IFNα/β in response to MYXV infection. To confirm IFNα/β did not play a role in this resistance, we ablated the ability of tumours to respond to IFNα/β via IRF9 knockdown, and generated identical results. Our studies demonstrate that these syngeneic cell lines are relevant preclinical models for testing experimental glioma treatments, and show that IFNα/β is not responsible for the MYXV treatment resistance seen in syngeneic glioma models.
authors.affiliation: Department of Oncology, Clark H. Smith Brain Tumor Center, University of Calgary, Tom Baker Cancer Centre, Southern Alberta Cancer Research Institute, Calgary, Alberta, Canada.
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Zemp
authors.forename: Brienne A
authors.initials: BA
authors.lastname: McKenzie
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.forename: Lori
authors.initials: L
authors.lastname: Maxwell
authors.forename: Karlyne M
authors.initials: KM
authors.lastname: Reilly
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology*; D005260:Female; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009233:Myxoma virus / Q000254:growth & development* / Q000276:immunology; D016900:Neurofilament Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050130:Oncolytic Virotherapy; D014185:Transplantation, Isogeneic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D016899:Interferon-beta; D016900:Neurofilament Proteins; D016159:Tumor Suppressor Protein p53; C044882:neurofilament protein L; C494228:Isgf3g protein, mouse