IFN-γ-Secreting-Mesenchymal Stem Cells Exert an Antitumor Effect In Vivo via the TRAIL Pathway

Mesenchymal stem cells (MSCs) can exhibit either prooncogenic or antitumor properties depending on the context. Based on our previous study, we hypothesized that MSCs engineered to deliver IFN-γ would kill cancer cells through persistent activation of the TRAIL pathway. Human bone-marrow (BM-) derived MSCs were isolated, amplified, and transduced with a lentiviral vector encoding the IFN-γ gene under the control of the EF1α promoter. The IFN-γ-modified MSCs effectively secreted functional IFN-γ, which led to long-term expression of TRAIL. More importantly, the IFN-γ-modified MSCs selectively induced apoptosis in lung tumor cells through caspase-3 activation within the target cells. The percentage of activated-caspase-3-positive tumor cells in IFN-γ-modified MSCs cocultures was significantly higher than in control MSCs cocultures. Treatment with anti-TRAIL antibody dramatically suppressed the caspase-3 activation observed in H460 cells. After injection into nude mice, the IFN-γ-modified MSCs inhibited the growth and progression of lung carcinoma compared with control cells. Collectively, our results provide a new strategy for tumor therapy that utilizes IFN-γ-modified MSCs.