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首页> 外文期刊>Molecular cancer therapeutics >Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Producing IL15 Eradicate Established Pancreatic Tumor in Syngeneic Mice
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Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Producing IL15 Eradicate Established Pancreatic Tumor in Syngeneic Mice

机译：人脐带血间充质干细胞产生IL15根除小鼠建立的同系小鼠胰腺肿瘤。

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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 naive 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. (C) 2014 AACR.
机译：间充质干细胞（MSC）代表了一种新的工具，可将治疗剂递送至癌症部位，因为它们对肿瘤的敏感性强。 IL15在各种动物模型以及临床试验中均显示出有效的抗肿瘤活性。然而，由于其半衰期短，有效的治疗效果通常需要高剂量，这通常会导致不良的副作用。因此，需要新的策略来克服这一缺点。在这项研究中，从脐带血中分离出人MSC作为输送载体，并用表达鼠IL15的慢病毒载体（MSC-IL15）进行了转导。淋巴细胞活化和增殖的体外测定表明，MSC产生的IL15具有生物功能。在患有Pan02胰腺肿瘤的同系小鼠中，全身给药MSC-IL15可显着抑制肿瘤生长并延长荷瘤小鼠的存活率，这与肿瘤细胞凋亡，自然杀伤（NK）和T细胞积累有关。此外，我们证实了MSC-IL15可以向肿瘤迁移并在肿瘤特异性位点分泌IL15。 NK和CD8（+）T细胞的耗竭消除了MSC-IL15的抗肿瘤活性，这表明NK和CD8（+）T细胞在MSC-IL15介导的作用中起着关键作用。有趣的是，经过MSC-IL15治疗的治愈小鼠对Pan02胰腺肿瘤的抵抗能力强，并且从治愈小鼠中过继转移淋巴细胞也可能导致幼稚小鼠中Pan02肿瘤接种的排斥，这表明MSC-IL15诱导了肿瘤特异性T细胞免疫记忆反应。总体而言，这些数据支持产生IL15的MSC可能代表了一种治疗胰腺肿瘤的创新策略。 （C）2014 AACR。

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