Peritumoral Administration of IFNβ Upregulated Mesenchymal Stem Cells Inhibits Tumor Growth in an Orthotopic, Immunocompetent Rat Glioma Model

BACKGROUND: Immunotherapy with IFNbeta is a promising strategy for treating malignant glioma. However, systemic administration of IFNbeta 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 IFNbeta for glioma therapy by using in vivo MRI tracking. METHODS: A recombinant lentiviral vector encoding IFNbeta and ferritin heavy chain (FTH) reporter genes was constructed to transduce MSCs. The effectiveness and safety of transduction were assessed. After the IFNbeta and FTH overexpressed MSCs (IFNbeta-FTH-MSCs) were transplanted into intracranial orthotopic rat F98 gliomas via peritumoral, intracerebral, intratumoral or intra-arterial injection, MRI was performed to track IFNbeta-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 IFNbeta secretion and FTH expression by the constructed lentivirus. After peritumoral injection, IFNbeta-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 IFNbeta-FTH-MSCs showed a remarkable inhibition on the glioma growth. Nearly 30% of IFNbeta-FTH-MSCs survived up to 11 days after peritumoral injection, while most of IFNbeta-FTH-MSCs injected via other routes died within 11 days. IFNbeta-FTH-MSCs grafted peritumorally secreted IFNbeta persistently, leading to pronounced Batf3(+) dendritic cells and CD8(+) T lymphocyte infiltration within the glioma. CONCLUSIONS: MSCs can be used as cellular vehicles of IFNbeta to treat malignant glioma effectively via peritumoral injection.