title: 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(+) T cells abolished the antitumor activity of MSC-IL15, suggesting that NK and CD8(+) 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 naïve 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.
authors.affiliation: Departments of General Surgery and.
authors.forename: Wei
authors.initials: W
authors.lastname: Jing
authors.affiliation: Radiotherapy, Changhai Hospital;
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, PLA No. 323 Hospital, Xi'an, Shaanxi;
authors.forename: Lei
authors.initials: L
authors.lastname: Lu
authors.affiliation: Departments of General Surgery and.
authors.forename: Xiangui
authors.initials: X
authors.lastname: Hu
authors.affiliation: Departments of General Surgery and.
authors.forename: Chenghao
authors.initials: C
authors.lastname: Shao
authors.affiliation: Departments of General Surgery and.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Departments of General Surgery and.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Departments of General Surgery and.
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Clinical and Translational Science, Mayo Clinic, Rochester Minnesota.
authors.forename: Lang
authors.initials: L
authors.lastname: Wu
authors.affiliation: Departments of General Surgery and.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: International Cancer Research Institute, The Second Military Medical University, Shanghai; Cancer Center, Chinese PLA General Hospital, Beijing, People's Republic of China; and jinggch@gmail.com kexingfan@gmail.com.
authors.forename: Kexing
authors.initials: K
authors.lastname: Fan
authors.affiliation: Departments of General Surgery and jinggch@gmail.com kexingfan@gmail.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Jin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: C569274:IL15 protein, human; D019409:Interleukin-15