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基因编辑多能干细胞来源的功能性T淋巴细胞的产生及其临床潜力

Generation and clinical potential of functional T lymphocytes from gene-edited pluripotent stem cells.

作者信息

Guo Rongqun, Li Wei, Li Yadan, Li Yingmei, Jiang Zhongxing, Song Yongping

机构信息

Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.

Academy of Medical Science, Henan Medical College of Zhengzhou University, Zhengzhou, 450052, Henan, China.

出版信息

Exp Hematol Oncol. 2022 May 14;11(1):27. doi: 10.1186/s40164-022-00285-y.


DOI:10.1186/s40164-022-00285-y
PMID:35568954
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9107657/
Abstract

Engineered T cells have been shown to be highly effective in cancer immunotherapy, although T cell exhaustion presents a challenge for their long-term function. Additional T-cell sources must be exploited to broaden the application of engineered T cells for immune defense and reconstitution. Unlimited sources of pluripotent stem cells (PSCs) have provided a potential opportunity to generate precise-engineered therapeutic induced T (iT) cells. Single-cell transcriptome analysis of PSC-derived induced hematopoietic stem and progenitor cells (iHSPC)/iT identified the developmental pathways and possibilities of generating functional T cell from PSCs. To date, the PSC-to-iT platforms encounter several problems, including low efficiency of conventional T subset specification, limited functional potential, and restrictions on large-scale application, because of the absence of a thymus-like organized microenvironment. The updated PSC-to-iT platforms, such as the three-dimensional (3D) artificial thymic organoid (ATO) co-culture system and Runx1/Hoxa9-enforced iT lymphopoiesis, provide fresh perspectives for coordinating culture conditions and transcription factors, which may greatly improve the efficiency of T-cell generation greatly. In addition, the improved PSC-to-iT platform coordinating gene editing technologies will provide various functional engineered unconventional or conventional T cells. Furthermore, the clinical applications of PSC-derived immune cells are accelerating from bench to bedside.

摘要

工程化T细胞已被证明在癌症免疫治疗中非常有效,尽管T细胞耗竭对其长期功能构成挑战。必须开发额外的T细胞来源,以扩大工程化T细胞在免疫防御和重建中的应用。多能干细胞(PSC)的无限来源为生成精确工程化的治疗性诱导T(iT)细胞提供了潜在机会。对PSC来源的诱导造血干细胞和祖细胞(iHSPC)/iT进行单细胞转录组分析,确定了从PSC生成功能性T细胞的发育途径和可能性。迄今为止,由于缺乏类似胸腺的有组织微环境,PSC到iT平台存在几个问题,包括传统T细胞亚群指定效率低、功能潜力有限以及大规模应用受限。更新后的PSC到iT平台,如三维(3D)人工胸腺类器官(ATO)共培养系统和Runx1/Hoxa9增强的iT淋巴细胞生成,为协调培养条件和转录因子提供了新的视角,这可能会大大提高T细胞生成的效率。此外,改进后的PSC到iT平台与基因编辑技术相结合,将提供各种功能性工程化非常规或常规T细胞。此外,PSC来源的免疫细胞的临床应用正在加速从实验室走向临床。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/edef1fb958b0/40164_2022_285_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/1ae41cd5a30c/40164_2022_285_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/cdc721760c70/40164_2022_285_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/edef1fb958b0/40164_2022_285_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/3987f9b07f83/40164_2022_285_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/26cee75688a4/40164_2022_285_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/7ec14f6093fe/40164_2022_285_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/39c3d96f0c2d/40164_2022_285_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/1ae41cd5a30c/40164_2022_285_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/cdc721760c70/40164_2022_285_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5c0d/9107657/edef1fb958b0/40164_2022_285_Fig7_HTML.jpg

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本文引用的文献

[1]
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Blood Sci. 2020-1-16

[2]
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J Hematol Oncol. 2021-10-30

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Gene Editing Rescues In vitro T Cell Development of RAG2-Deficient Induced Pluripotent Stem Cells in an Artificial Thymic Organoid System.

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