Interleukin (IL)-21, a proinflammatory
cytokine, has been developed as an immunotherapeutic approach due to its effects on various lymphocytes, including natural killer (NK) cells and T cells; however, the clinical success in
cancer patients has been limited. Recently, mesenchymal stem cells (MSCs) have emerged as vehicles for cancer gene
therapy due to their inherent migratory abilities toward
tumors. In the present study, we hypothesized that MSCs, genetically modified to express high levels of
IL-21 (IL-21/MSCs), can enhance antitumor responses through localized delivery of
IL-21. For
tumor induction, BALB/c mice were injected intravenously with syngeneic A20
B-cell lymphoma cells to develop a disseminated
B-cell lymphoma model. Then, 6 days following
tumor induction, the
tumor-bearing mice were treated with IL-21/MSCs weekly, four times. Systemic infusion of A20 cells led to hind-leg
paralysis as well as severe liver
metastasis in the control group. The IL-21/MSC-treated group showed delayed
tumor incidence as well as improved survival, whereas the MSC- and recombinant adenovirus-expressing
IL-21 (rAD/IL-21)-treated groups did not show significant differences from the untreated mice. These
therapeutic effects were associated with high levels of
IL-21 delivered to the liver, which prevented the formation of
tumor nodules. Furthermore, the infusion of IL-21/MSCs led to induction of effector T and NK cells, while potently inhibiting immune suppressor cells. Our findings demonstrate that IL-21-expressing MSCs have the therapeutic potential to induce potent antitumor effects against disseminated
B-cell lymphoma through localized
IL-21 delivery and induction of systemic antitumor immunity.