Developmental Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
ARTEC Biotech Inc, Chicago, IL, USA.
Oncoimmunology. 2023 Sep 12;12(1):2240670. doi: 10.1080/2162402X.2023.2240670. eCollection 2023.
Immunotherapeutic innovation is crucial for limited operability tumors. CAR T-cell therapy displayed reduced efficiency against glioblastoma (GBM), likely due to mutations underlying disease progression. Natural Killer cells (NKs) detect cancer cells despite said mutations - demonstrating increased tumor elimination potential. We developed an NK differentiation system using human pluripotent stem cells (hPSCs). Via this system, genetic modifications targeting cancer treatment challenges can be introduced during pluripotency - enabling unlimited production of modified "off-the-shelf" hPSC-NKs.
hPSCs were differentiated into hematopoietic progenitor cells (HPCs) and NKs using our novel organoid system. These cells were characterized using flow cytometric and bioinformatic analyses. HPC engraftment potential was assessed using NSG mice. NK cytotoxicity was validated using and K562 assays and further corroborated on lymphoma, diffuse intrinsic pontine glioma (DIPG), and GBM cell lines .
HPCs demonstrated engraftment in peripheral blood samples, and hPSC-NKs showcased morphology and functionality akin to same donor peripheral blood NKs (PB-NKs). The hPSC-NKs also displayed potential advantages regarding checkpoint inhibitor and metabolic gene expression, and demonstrated and cytotoxicity against various cancers.
Our organoid system, designed to replicate cellular organization (including signaling gradients and shear stress conditions), offers a suitable environment for HPC and NK generation. The engraftable nature of HPCs and potent NK cytotoxicity against leukemia, lymphoma, DIPG, and GBM highlight the potential of this innovative system to serve as a valuable tool that will benefit cancer treatment and research - improving patient survival and quality of life.
免疫治疗创新对于可操作性有限的肿瘤至关重要。嵌合抗原受体 T 细胞（CAR T）疗法对胶质母细胞瘤（GBM）的疗效降低，可能是由于疾病进展所导致的突变。自然杀伤细胞（NK）能够检测到癌细胞，尽管存在这些突变，这表明其具有更强的肿瘤消除潜力。我们使用人类多能干细胞（hPSC）开发了一种 NK 分化系统。通过该系统，可以在多能性阶段引入针对癌症治疗挑战的基因修饰，从而实现修饰后的“现货”hPSC-NK 的无限生产。
我们使用新型类器官系统将 hPSC 分化为造血祖细胞（HPC）和 NK。使用流式细胞术和生物信息学分析对这些细胞进行了表征。通过 NSG 小鼠评估了 HPC 的植入潜力。通过 和 K562 测定法验证了 NK 的细胞毒性，并进一步在淋巴瘤、弥漫性内在脑桥胶质瘤（DIPG）和 GBM 细胞系上进行了验证。
HPC 在外周血样本中显示出植入能力，hPSC-NK 表现出与同供体外周血 NK（PB-NK）相似的形态和功能。hPSC-NK 还在检查点抑制剂和代谢基因表达方面表现出潜在优势，并显示出对各种癌症的 和 细胞毒性。
我们的类器官系统旨在复制细胞组织（包括信号梯度和切应力条件），为 HPC 和 NK 的产生提供了合适的环境。HPC 的可植入性和对白血病、淋巴瘤、DIPG 和 GBM 的强大 NK 细胞毒性突出了该创新系统作为一种有价值的工具的潜力，将有益于癌症治疗和研究，提高患者的生存率和生活质量。
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