Resistance to Oncolytic Myxoma Virus Therapy in Nf1−/−/Trp53−/− Syngeneic Mouse Glioma Models Is Independent of Anti-Viral Type-I Interferon

摘要: Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results clinical evaluations. Of concern are the low levels of tumour infection and replication within tumour. This discrepancy between laboratory clinic could result from disparity xenograft versus syngeneic models determining vivo infection, treatment efficacy. Here we describe a panel primary mouse glioma lines derived Nf1+/−Trp53+/− mice C57Bl/6J background use testing virus Myxoma (MYXV). These show range susceptibility to MYXV vitro, all succumb viral-mediated cell death. Two these orthotopically grafted produced aggressive gliomas. Intracranial injection failed sustained or efficacy, with minimal that was completely resolved by 7 days post-infection. We hypothesized stromal production Type-I interferons (IFNα/β) explain resistance seen models; however, found neither vitro nor tumours produce any IFNα/β response infection. To confirm did not play role this resistance, ablated ability respond via IRF9 knockdown, generated identical results. Our studies demonstrate relevant experimental treatments, is responsible models.