近日，美国明尼苏达大学Jeffrey S. Miller团队发现，利用适应性NK细胞的特点产生iPSC来源的NK细胞可增强免疫治疗效果。2021年9月14日，国际知名学术期刊《细胞—干细胞》在线发表了这一成果。

研究人员表示，免疫效应细胞特定亚群具有介导抗肿瘤反应的最大倾向。然而，获取这些亚群是具有挑战性的，而且基于细胞的免疫疗法因效应细胞的持久性有限和缺乏可用性而受到阻碍。

为了解决这些限制，研究人员产生了一个三基因编辑的诱导多能干细胞（iPSC）。该克隆iPSC系被设计为表达一个高亲和力、不可清除的Fc受体CD16a版本和一个膜结合的白细胞介素（IL）-15/IL-15R融合蛋白。第三种编辑是对水解NAD⁺的胞外酶CD38的敲除。从这些统一设计的iPSC来源的自然杀伤（NK）细胞，被称为iADAPT，显示出代谢特征和基因表达谱，反映了巨细胞病毒诱导的适应性NK细胞特征。iADAPT NK细胞在没有外源细胞因子的情况下在体内持续存在，并引起显著的抗肿瘤活性。

这些研究结果表明，免疫系统的独特亚群可以通过iPSC技术建立模型，从而有效治疗晚期癌症患者。

附：英文原文

Title: Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy

Author: Karrune V. Woan, Hansol Kim, Ryan Bjordahl, Zachary B. Davis, Svetlana Gaidarova, John Goulding, Brian Hancock, Sajid Mahmood, Ramzey Abujarour, Hongbo Wang, Katie Tuininga, Bin Zhang, Cheng-Ying Wu, Behiye Kodal, Melissa Khaw, Laura Bendzick, Paul Rogers, Moyar Qing Ge, Greg Bonello, Miguel Meza, Martin Felices, Janel Huffman, Thomas Dailey, Tom T. Lee, Bruce Walcheck, Karl J. Malmberg, Bruce R. Blazar, Yenan T. Bryceson, Bahram Valamehr, Jeffrey S. Miller, Frank Cichocki

Issue&Volume: 2021-09-14

Abstract: Select subsets of immune effector cells have the greatest propensity to mediate antitumorresponses. However, procuring these subsets is challenging, and cell-based immunotherapyis hampered by limited effector-cell persistence and lack of on-demand availability.To address these limitations, we generated a triple-gene-edited induced pluripotentstem cell (iPSC). The clonal iPSC line was engineered to express a high affinity,non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15Rfusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzesNAD+. Natural killer (NK) cells derived from these uniformly engineered iPSCs, termediADAPT, displayed metabolic features and gene expression profiles mirroring thoseof cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Ourfindings suggest that unique subsets of the immune system can be modeled through iPSCtechnology for effective treatment of patients with advanced cancer.

DOI: 10.1016/j.stem.2021.08.013

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00350-7