Large-scale generation of IL12 secreting macrophages from human pluripotent stem cells for cancer therapy

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy-Methods & Clinical Development Pub Date : 2024-02-02 DOI:10.1016/j.omtm.2024.101204

Baoqiang Kang, Qi Xing, Yuhua Huang, Huaisong Lin, Jiaojiao Peng, Zhishuai Zhang, Mingquan Wang, Xinrui Guo, Xing Hu, Shuoting Wang, Junwei Wang, Minghui Gao, Yanling Zhu, Guangjin Pan

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Abstract

Genetically engineered macrophages (GEMs) have emerged as an appealing strategy to treat cancers, but are largely impeded by the cell availability and technical challenges in gene transfer. Here, we develop an efficient approach to generate large-scale macrophages from human induced pluripotent stem cells (hiPSCs). Starting with 1 T150 dish of 10⁶ hiPSCs, more than 10⁹ mature macrophages (iMacs) could be generated within 1 month. The generated iMacs exhibit typical macrophage properties such as phagocytosis and polarization. We then generate hiPSCs integrated with an IL12 expression cassette in AAVS1 locus to produce iMacs secreting IL12, a strong pro-immunity cytokine. hiPSCs derived iMacs_IL12 prevent cytotoxic T cell exhaustion and activate T cells to kill different cancer cells. Furthermore, iMACs_IL12 display strong anti-tumor effects in a T cell dependent manner in subcutaneously or systemically xenografted mice of human lung cancer. Therefore, we provide an off-the-shelf strategy to produce large-scale GEMs for cancer therapy.

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利用人体多能干细胞大规模生成分泌 IL12 的巨噬细胞，用于癌症治疗

基因工程巨噬细胞（GEMs）已成为治疗癌症的一种有吸引力的策略，但在很大程度上受到细胞可用性和基因转移技术挑战的阻碍。在这里，我们开发了一种从人类诱导多能干细胞（hiPSCs）生成大规模巨噬细胞的高效方法。从1个T150平皿的106个hiPSCs开始，1个月内可生成超过109个成熟的巨噬细胞（iMacs）。生成的 iMacs 具有典型的巨噬细胞特性，如吞噬和极化。然后，我们生成了在 AAVS1 基因座上整合了 IL12 表达盒的 hiPSCs，产生了能分泌 IL12（一种强免疫细胞因子）的 iMacs。此外，iMACs_IL12 在皮下或全身异种移植人类肺癌小鼠中以依赖 T 细胞的方式显示出强大的抗肿瘤作用。因此，我们提供了一种现成的策略来生产用于癌症治疗的大规模 GEMs。

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来源期刊

Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.90

自引率

4.30%

发文量

163

审稿时长

12 weeks

期刊介绍： The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.