Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells Producing IL15 Eradicate Established Pancreatic Tumor in Syngeneic Mice

Abstract

Mesenchymal stem cells (MSC) represent a new tool for delivery of therapeutic agents to cancer sites because of their strong tropism toward tumors. IL15 has demonstrated a potent antitumor 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 IL15 (MSC-IL15). In vitro assays of lymphocyte activation and proliferation demonstrated that IL15 produced by MSCs was biofunctional. In syngeneic mice bearing Pan02 pancreatic tumors, systemic administration of MSC-IL15 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice, which were associated with tumor cell apoptosis, and natural killer (NK)-and T-cell accumulation. Furthermore, we confirmed that MSC-IL15 could migrate toward tumor and secreted IL15 in tumor-specific sites. Depletion of NK and CD8 þ T cells abolished the antitumor activity of MSC-IL15, suggesting that NK and CD8 þ T cells play a key role for MSC-IL15-mediated effect. Interestingly, cured mice after MSC-IL15 treatment were resistant to Pan02 pancreatic tumor rechallenge, and adoptive transfer of lymphocytes from cured mice also could cause rejection of Pan02 tumor inoculation in na€ ve mice, indicating that MSC-IL15 induced tumor-specific T-cell immune memory response. Overall, these data support that MSCs producing IL15 might represent an innovative strategy for therapy of pancreatic tumor.

Human-derived normal mesenchymal stem/stromal cells in anticancer therapies

“…However, artificial fusion of MSCs with esophageal carcinoma cell line EC9706 resulted in hybrids with declined cell growth, increased apoptosis and suppressed tumorigenicity 31. UC-MSCs promote the proliferation of mouse pancreatic cancer cell line Pan02 in vivo , however, MSCs producing IL-15 eradicate established pancreatic tumors in syngeneic mice 32.…”

The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

“…Additionally, it has been reported that umbilical cord MSCs with previously enhanced IL-15 gene expression significantly suppresses pancreatic tumor growth in mice. Moreover, in this study it has been demonstrated that MSCs, induced for IL-15 expression, stimulate accumulation of NK cells and CD8 + T lymphocytes, thus supporting antitumor immune response [133]. Also, it has been shown that IFN- β -producing MSCs from bone marrow [134], as well as adipose tissue [135], inhibit proliferation of hepatocellular carcinoma or breast cancer, respectively.…”

Functional beta-cells derived from umbilical cord blood mesenchymal stem cells for curing rats with streptozotocin-induced diabetes mellitus

“…(20,21) In our study, the UCBMSCs were preferred over the other stem cell types due to their unique advantages, such as painless collection procedure, easy availability, high efficiency of differentiation and faster self-renewal, with lower risk for graft versus host disease. (22) Studies by Sun et al (23) and Jing et al (24) showed that these cells, when transplanted into normal rat tissues, failed to produce tumours or any immune rejection response. Moreover, reports on the efficiency of UCBMSCs for the treatment of various injuries and diseases, both clinically and pre-clinically, have been documented in the recent past.…”