K562细胞
白细胞介素15
生物
细胞因子
自然杀伤细胞
免疫学
免疫疗法
表型
白细胞介素21
功能(生物学)
细胞毒性
转基因
细胞生物学
转录组
癌症研究
体外
白细胞介素
T细胞
免疫系统
基因
基因表达
白血病
生物化学
作者
Caimei Zhang,Siddhant Kadu,Yansen Xiao,Omar Johnson,Andre Kelly,Roddy S. O’Connor,Meizan Lai,Hong Kong,Sriram Srivatsa,Victoria Tai,Eli Greenblatt,Matthew Holmes,James L. Riley,Carl H. June,Neil C. Sheppard
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2023-08-30
卷期号:11 (11): 1524-1537
被引量:5
标识
DOI:10.1158/2326-6066.cir-23-0151
摘要
Abstract Natural killer (NK) cells are frequently expanded for the clinic using irradiated, engineered K562 feeder cells expressing a core transgene set of membrane-bound (mb) IL15 and/or mbIL21 together with 41BBL. Prior comparisons of mbIL15 to mbIL21 for NK expansion lack comparisons of key attributes of the resulting NK cells, including their high-dimensional phenotype, polyfunctionality, the breadth and potency of cytotoxicity, cellular metabolism, and activity in xenograft tumor models. Moreover, despite multiple rounds of K562 stimulation, studies of sequential use of mbIL15- and mbIL21-based feeder cells are absent. We addressed these gaps and found that using mbIL15- versus mbIL21-based feeder cells drove distinct phenotypic and functional profiles. Feeder cells expressing mbIL15 alone drove superior functionality by nearly all measures, whereas those expressing mbIL21 alone drove superior yield. In combination, most attributes resembled those imparted by mbIL21, whereas in sequence, NK yield approximated that imparted by the first cytokine, and the phenotype, transcriptome, and function resembled that driven by the second cytokine, highlighting the plasticity of NK cell differentiation. The sequence mbIL21 followed by mbIL15 was advantageous in achieving significant yields of highly functional NK cells that demonstrated equivalent in vivo activity to those expanded by mbIL15 alone in two of three xenograft models. Our findings define the impact of mbIL15 versus mbIL21 during NK expansion and reveal a previously underappreciated tradeoff between NK yield and function for which sequential use of mbIL21-based followed by mbIL15-based feeder cells may be the optimal approach in many settings.
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