Large-scale generation of IL-12 secreting macrophages from human pluripotent stem cells for cancer therapy

Genetically engineered macrophages (GEMs) have emerged as an appealing strategy to treat cancers, but they 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...

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Published in:Molecular therapy. Methods & clinical development 2024-03, Vol.32 (1), p.101204, Article 101204
Main Authors: Kang, Baoqiang, Xing, Qi, Huang, Yuhua, Lin, Huaisong, Peng, Jiaojiao, Zhang, Zhishuai, Wang, Mingquan, Guo, Xinrui, Hu, Xing, Wang, Shuoting, Wang, Junwei, Gao, Minghui, Zhu, Yanling, Pan, Guangjin
Format: Article
Language:English
Subjects:
cancer immunotherapy
CRISPR-Cas9
IL-12
iPSCs differentiation
macrophage
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Summary:Genetically engineered macrophages (GEMs) have emerged as an appealing strategy to treat cancers, but they 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 IL-12 expression cassette in the AAVS1 locus to produce iMacs secreting IL-12, a strong proimmunity cytokine. hiPSC-derived iMacs_IL-12 prevent cytotoxic T cell exhaustion and activate T cells to kill different cancer cells. Furthermore, iMacs_IL-12 display strong antitumor 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. [Display omitted] Kang and colleagues generated hiPSCs integrated with an IL-12 expression cassette to produce iMacs secreting IL-12 by large-scale macrophages’ efficient differentiation approach. iMacs_IL-12 display antitumor effects by activating and preventing cytotoxic T cell exhaustion in vitro and subcutaneously or systemically xenografted mice of human cancer.
ISSN:2329-0501
2329-0501
DOI:10.1016/j.omtm.2024.101204