Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR-S-1310), Villejuif, France.
Unités Mixtes de Service (UMS 045)- CITHERA (Center for iPSC Cell Therapy), National Infrastructure INGESTEM, Corbeil-Essonnes, Evry, France.
Front Immunol. 2024 Oct 9;15:1463736. doi: 10.3389/fimmu.2024.1463736. eCollection 2024.
The ability to generate natural killer (NK) cells from induced pluripotent stem cells (iPSCs) has given rise to new possibilities for the large-scale production of homogeneous immunotherapeutic cellular products and opened new avenues towards the creation of "off-the-shelf" cancer immunotherapies. However, the differentiation of NK cells from iPSCs remains poorly understood, particularly regarding the ontogenic landscape of iPSC-derived NK (iNK) cells produced and the influence that the differentiation strategy employed may have on the iNK profile.
To investigate this question, we conducted a comparative analysis of two sets of iNK cells generated from the same iPSC line using two different protocols: (i) a short-term, clinically compatible feeder-free protocol corresponding to primitive hematopoiesis, and (ii) a lymphoid-based protocol representing the definitive hematopoietic step.
Our work demonstrated that both protocols are capable of producing functional iNK cells. However, the two sets of resulting iNKs exhibited distinct phenotypes and transcriptomic profiles. The lymphoid-based differentiation approach generated iNKs with a more mature and activated profile, which demonstrated higher cytotoxicity against cancer cell lines compared to iNK cells produced under short-term feeder-free conditions suggesting that the differentiation strategy must be considered when designing iNK cell-based adoptive immunotherapies.
诱导多能干细胞（iPSCs）产生自然杀伤（NK）细胞的能力为大规模生产同质免疫治疗细胞产品带来了新的可能性，并为创建“现货”癌症免疫疗法开辟了新的途径。然而，iPSCs 向 NK 细胞的分化仍知之甚少，特别是关于产生的 iPSC 来源的 NK（iNK）细胞的个体发生景观，以及所采用的分化策略可能对 iNK 特征的影响。
为了研究这个问题，我们使用两种不同的方案对同一 iPSC 系产生的两组 iNK 细胞进行了比较分析：（i）一种短期的、临床兼容的无饲养层方案，对应于原始造血；（ii）一种基于淋巴样的方案，代表确定性造血步骤。
我们的工作表明，这两种方案都能够产生功能性的 iNK 细胞。然而，两组产生的 iNK 细胞表现出不同的表型和转录组特征。基于淋巴样的分化方法产生的 iNK 细胞具有更成熟和激活的特征，与短期无饲养层条件下产生的 iNK 细胞相比，对癌细胞系的细胞毒性更高，这表明在设计基于 iNK 细胞的过继免疫疗法时，必须考虑分化策略。
