{"title":"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","authors":"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","doi":"10.1016/j.omtm.2024.101204","DOIUrl":null,"url":null,"abstract":"<p>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 10<sup>6</sup> hiPSCs, more than 10<sup>9</sup> 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.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Large-scale generation of IL12 secreting macrophages from human pluripotent stem cells for cancer therapy\",\"authors\":\"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\",\"doi\":\"10.1016/j.omtm.2024.101204\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>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 10<sup>6</sup> hiPSCs, more than 10<sup>9</sup> 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.</p>\",\"PeriodicalId\":54333,\"journal\":{\"name\":\"Molecular Therapy-Methods & Clinical Development\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-02-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Therapy-Methods & Clinical Development\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.omtm.2024.101204\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy-Methods & Clinical Development","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.omtm.2024.101204","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Large-scale generation of IL12 secreting macrophages from human pluripotent stem cells for cancer therapy
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.
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.
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