Feeder-free differentiation of human iPSCs into natural killer cells with cytotoxic potential against malignant brain rhabdoid tumor cells
Feeder-free differentiation of human iPSCs into natural killer cells with cytotoxic potential against malignant brain rhabdoid tumor cells
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DOI：
10.1016/j.bioactmat.2024.02.031
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发表时间：
2024-06-01
影响因子：
18.9
通讯作者：
Sang，Qing-Xiang Amy
中科院分区：
文献类型：
--
作者：
Kiran，Sonia;Xue，Yu;Sang，Qing-Xiang Amy
自然杀伤（NK）细胞是细胞毒性免疫细胞，可以消除靶细胞，而无需事先刺激。人类诱导多能干细胞（iPSC）为针对侵袭性癌症的安全有效的基于细胞的免疫疗法提供了强大的NK细胞来源。在该体外研究中，进行无饲养层iPSC分化以获得iPSC-NK细胞，并表征iPSC-NK的不同成熟阶段。在IL-15暴露后，CD 56 brightCD 16 brightphenotype的成熟细胞显示出CD 56、CD 16和NK细胞活化标志物NKG 2D和NKp 46的上调，而暴露于侵袭性非典型畸胎瘤/横纹肌样瘤（ATRT）细胞系则增强了NKG 2D和NKp 46的表达。恶性细胞暴露还增加了活化的NK细胞中的CD 107 a脱粒标志物并刺激IFN-γ分泌。CD 56 brightCD 16 brightPSC-NK细胞显示出对ATRT细胞的比率依赖性杀伤，并且CHLA-05-ATRT的裂解百分比高于CHLA-02-ATRT的裂解百分比。iPSC-NK细胞对其他脑、肾和肺癌细胞系也具有细胞毒性。进一步的NK成熟产生了CD 56 − veCD 16亮细胞，即使暴露于白细胞介素或ATRT细胞后也缺乏活化标记物-表明细胞毒性减弱。来自iPSC的不同NK表型的产生和表征，加上它们在体外对ATRT的有希望的抗肿瘤活性，为脑肿瘤的潜在免疫策略提供了有价值的见解。
Natural killer (NK) cells are cytotoxic immune cells that can eliminate target cells without prior stimulation. Human induced pluripotent stem cells (iPSCs) provide a robust source of NK cells for safe and effective cell-based immunotherapy against aggressive cancers. In thisin vitrostudy, a feeder-free iPSC differentiation was performed to obtain iPSC-NK cells, and distinct maturational stages of iPSC-NK were characterized. Mature cells of CD56brightCD16brightphenotype showed upregulation of CD56, CD16, and NK cell activation markers NKG2D and NKp46 upon IL-15 exposure, while exposure to aggressive atypical teratoid/rhabdoid tumor (ATRT) cell lines enhanced NKG2D and NKp46 expression. Malignant cell exposure also increased CD107a degranulation markers and stimulated IFN-γ secretion in activated NK cells. CD56brightCD16brightiPSC-NK cells showed a ratio-dependent killing of ATRT cells, and the percentage lysis of CHLA-05-ATRT was higher than that of CHLA-02-ATRT. The iPSC-NK cells were also cytotoxic against other brain, kidney, and lung cancer cell lines. Further NK maturation yielded CD56−veCD16brightcells, which lacked activation markers even after exposure to interleukins or ATRT cells - indicating diminished cytotoxicity. Generation and characterization of different NK phenotypes from iPSCs, coupled with their promising anti-tumor activity against ATRTin vitro, offer valuable insights into potential immunotherapeutic strategies for brain tumors.