Large-scale generation of IL-12 secreting macrophages from human pluripotent stem cells for cancer therapy
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
Abstract
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 10 6 hiPSCs, more than 10 9 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.