Clinical-Scale Derivation of Natural Killer Cells From Human Pluripotent Stem Cells for Cancer Therapy
Clinical-Scale Derivation of Natural Killer Cells From Human Pluripotent Stem Cells for Cancer Therapy
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DOI：
10.5966/sctm.2012-0084
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发表时间：
2013-04-01
影响因子：
6
通讯作者：
Kaufman, Dan S.
中科院分区：
文献类型：
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作者：
Knorr, David A.;Ni, Zhenya;Kaufman, Dan S.
在过去的二十年中，抗肿瘤淋巴细胞的过继转移引起了癌症治疗领域的浓厚兴趣。人类自然杀伤（NK）细胞是用于抗癌免疫治疗的有前途的淋巴细胞来源。 NK 细胞是先天免疫系统的一部分，无需人类白细胞抗原匹配且无需事先暴露抗原，即可表现出有效的抗肿瘤活性。此外，从多能干细胞中衍生出 NK 细胞可以为现成的治疗提供无限的淋巴细胞来源。迄今为止，大多数关于人类胚胎干细胞 (hESC) 和诱导多能干细胞 (iPSC) 造血细胞发育的研究所使用的条件不完全明确，且规模有限。在这里，我们使用两阶段培养系统，在没有细胞分选且不需要异种基质细胞的情况下，从 hESC 和 iPSC 中高效生产 NK 细胞。这种使用规定条件和表达膜结合白细胞介素 21 的人工抗原呈递细胞形成胚状体的新组合，允许从几种不同的 hESC 和 iPSC 系中产生成熟且有功能的 NK 细胞。尽管不同的 hESC 和 iPSC 系在造血发育方面具有不同的效率，但所有测试的细胞系都可以产生功能性 NK 细胞。这些方法可用于从少于 250,000 个输入 hESC/iPSC 中产生足够的细胞毒性 NK 细胞来治疗单个患者。此外，该策略提供了一个适合遗传的平台来研究正常 NK 细胞的体外发育和教育。干细胞转化医学 2013；2:274-283
Adoptive transfer of antitumor lymphocytes has gained intense interest in the field of cancer therapeutics over the past two decades. Human natural killer (NK) cells are a promising source of lymphocytes for anticancer immunotherapy. NK cells are part of the innate immune system and exhibit potent antitumor activity without need for human leukocyte antigen matching and without prior antigen exposure. More-over, the derivation of NK cells from pluripotent stem cells could provide an unlimited source of lymphocytes for off-the-shelf therapy. To date, most studies on hematopoietic cell development from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) have used incompletely defined conditions and been on a limited scale. Here, we have used a two-stage culture system to efficiently produce NK cells from hESCs and iPSCs in the absence of cell sorting and without need for xenogeneic stromal cells. This novel combination of embryoid body formation using defined conditions and membrane-bound interleukin 21-expressing artificial antigen-presenting cells allows production of mature and functional NK cells from several different hESC and iPSC lines. Although different hESC and iPSC lines had varying efficiencies in hematopoietic development, all cell lines tested could produce functional NK cells. These methods can be used to generate enough cytotoxic NK cells to treat a single patient from fewer than 250,000 input hESCs/iPSCs. Additionally, this strategy provides a genetically amenable platform to study normal NK cell development and education in vitro. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:274-283