Peritumoral administration of IFNβ upregulated mesenchymal stem cells inhibits tumor growth in an orthotopic, immunocompetent rat glioma model

Abstract

Background Immunotherapy with IFN beta is a promising strategy for treating malignant glioma. However, systemic administration of IFN beta is inadequate because of low intratumoral concentration and major adverse effects. This study aimed to determine whether mesenchymal stem cells (MSCs) can be used as cellular vehicles to locally deliver IFN beta for glioma therapy by using in vivo MRI tracking. Methods A recombinant lentiviral vector encoding IFN beta and ferritin heavy chain (FTH) reporter genes was constructed to transduce MSCs. The effectiveness and safety of transduction were assessed. After the IFN beta and FTH overexpressed MSCs (IFN beta-FTH-MSCs) were transplanted into intracranial orthotopic rat F98 gliomas via peritumoral, intracerebral, intratumoral or intra-arterial injection, MRI was performed to track IFN beta-FTH-MSCs and to evaluate their therapeutic effect on glioma in vivo, as validated by histologic analysis, quantitative PCR and ELISA assays. Results MSCs were efficiently and safely transduced to upregulate their IFN beta secretion and FTH expression by the constructed lentivirus. After peritumoral injection, IFN beta-FTH-MSCs appeared as hypointense signals on MRI, which gradually diminished but remained visible until 11 days. Compared with other administration routes, only peritumoral injection of IFN beta-FTH-MSCs showed a remarkable inhibition on the glioma growth. Nearly 30% of IFN beta-FTH-MSCs survived up to 11 days after peritumoral injection, while most of IFN beta-FTH-MSCs injected via other routes died within 11 days. IFN beta-FTH-MSCs grafted peritumorally secreted IFN beta persistently, leading to pronounced Batf3(+) dendritic cells and CD8(+) T lymphocyte infiltration within the glioma. Conclusions MSCs can be used as cellular vehicles of IFN beta to treat malignant glioma effectively via peritumoral injection.