In vitro vascular differentiation system efficiently produces natural killer cells for cancer immunotherapies.

IF 7.2 2区医学 Oncoimmunology Pub Date : 2023-09-12 eCollection Date: 2023-01-01 DOI:10.1080/2162402X.2023.2240670

Yekaterina Galat, Yuchen Du, Mariana Perepitchka, Xiao-Nan Li, Irina V Balyasnikova, William T Tse, Svetlana Dambaeva, Sylvia Schneiderman, Philip M Iannaccone, Oren Becher, Douglas K Graham, Vasiliy Galat

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Abstract

Background: 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.

Methods: 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 in vitro and in vitro K562 assays and further corroborated on lymphoma, diffuse intrinsic pontine glioma (DIPG), and GBM cell lines in vitro.

Results: 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 in vitro and in vivo cytotoxicity against various cancers.

Conclusions: Our organoid system, designed to replicate in vivo 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.

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体外血管分化系统有效地产生用于癌症免疫治疗的自然杀伤细胞。

背景：免疫治疗创新对于可操作性有限的肿瘤至关重要。CAR T细胞治疗对胶质母细胞瘤（GBM）的疗效降低，这可能是由于疾病进展背后的突变。自然杀伤细胞（NK）检测到癌症细胞，尽管有上述突变，这表明肿瘤消除潜力增加。我们使用人多能干细胞（hPSCs）开发了NK分化系统。通过该系统，可以在多能性过程中引入针对癌症治疗挑战的基因修饰，从而无限制地产生修饰的“离体”hPSC-NK。方法：使用我们的新型类器官系统，将hPSC-分化为造血祖细胞（HPCs）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。使用NSG小鼠评估HPC植入潜力。使用体外和体外K562测定验证了NK细胞的细胞毒性，并在淋巴瘤、弥漫性固有桥脑胶质瘤（DIPG）和GBM细胞系上进一步证实了其细胞毒性。结果：HPCs在外周血样本中表现出植入，hPSC NKs表现出类似于同一供体外周血NKs（PB NKs）的形态和功能。hPSC NKs在检查点抑制剂和代谢基因表达方面也显示出潜在的优势，并在体外和体内表现出对各种癌症的细胞毒性。结论：我们的类器官系统旨在复制体内细胞组织（包括信号梯度和剪切应力条件），为HPC和NK的产生提供了合适的环境。HPCs的可移植性和对白血病、淋巴瘤、DIPG和GBM的强大NK细胞毒性突出了这一创新系统作为有益于癌症治疗和研究的宝贵工具的潜力，提高了患者生存率和生活质量。

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来源期刊

Oncoimmunology ONCOLOGY-IMMUNOLOGY

CiteScore

12.80

自引率

2.80%

发文量

276

期刊介绍： Tumor immunology explores the natural and therapy-induced recognition of cancers, along with the complex interplay between oncogenesis, inflammation, and immunosurveillance. In response to recent advancements, a new journal, OncoImmunology, is being launched to specifically address tumor immunology. The field has seen significant progress with the clinical demonstration and FDA approval of anticancer immunotherapies. There's also growing evidence suggesting that many current chemotherapeutic agents rely on immune effectors for their efficacy. While oncologists have historically utilized chemotherapeutic and radiotherapeutic regimens successfully, they may have unwittingly leveraged the immune system's ability to recognize tumor-specific antigens and control cancer growth. Consequently, immunological biomarkers are increasingly crucial for cancer prognosis and predicting chemotherapy efficacy. There's strong support for combining conventional anticancer therapies with immunotherapies. OncoImmunology will welcome high-profile submissions spanning fundamental, translational, and clinical aspects of tumor immunology, including solid and hematological cancers, inflammation, and both innate and acquired immune responses.