Human umbilical cord blood- derived mesenchymal stem cells producing IL-15 eradicate established pancreatic tumor in syngeneic mice

Abstract

Mesenchymal stem cells (MSCs) represent a new tool for delivery of therapeutic agents to cancer sites due to their strong tropism toward tumors. Interleukin-15 (IL-15) has demonstrated a potent anti-tumor activity in various animal models as well as clinical trials. However, because of its short half-life, effective therapeutic effects usually require a high dose which often results in undesired side effects, thus new strategies for overcoming this disadvantage are needed. In this study, human MSCs were isolated from umbilical cord blood as delivery vehicles, and transduced with lentivirus vector expressing murine IL-15 (MSC-IL-15). In vitro assays of lymphocyte activation and proliferation demonstrated that IL-15 produced by MSCs was biofunctional. In syngeneic mice bearing Pan02 pancreatic tumors, systemic administration of MSC-IL-15 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice, which were associated with tumor cell apoptosis, and NK and T cell accumulation. Furthermore, we confirmed that MSC- IL-15 could migrate toward tumor and secreted IL-15 in tumor specific sites. Depletion of NK and CD8+ T cells abolished the anti-tumor activity of MSC-IL-15, suggesting that NK and CD8+ T cells play a key role for MSC-IL-15 -mediated effect. Interestingly, cured mice after MSC-IL-15 treatment were resistant to Pan02 pancreatic tumor rechallenge, and adoptive transfer of lymphocytes from cured mice also could reject Pan02 tumor inoculation in naïve mice, indicating that MSC-IL-15 induced tumor-specific T-cell immune memory response. Overall, these data supported that MSCs producing IL-15 might represent an innovative strategy for therapy of pancreatic tumor.