肿瘤细胞治疗研究
英文原题：Large-scale generation of IL-12 secreting macrophages from human pluripotent stem cells for cancer therapy.
Large-scale generation of IL-12 secreting macrophages from human pluripotent stem cells for cancer therapy.
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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，但其在很大程度上受到细胞可获得性和基因转移技术挑战的阻碍。
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，但其在很大程度上受到细胞可获得性和基因转移技术挑战的阻碍。在此，我们开发了一种高效的方法，从人诱导多能干细胞（hiPSCs）大规模生成巨噬细胞。从1个T150培养皿中的10 6个hiPSCs开始，可在1个月内生成超过10 9个成熟巨噬细胞（iMacs）。生成的iMacs表现出典型的巨噬细胞特性，如吞噬作用和极化。随后，我们生成了在AAVS1位点整合IL-12表达盒的hiPSCs，以产生分泌IL-12的iMacs，IL-12是一种强效促免疫细胞因子。hiPSC来源的iMacs_IL-12可防止细胞毒性T细胞耗竭，并激活T细胞杀伤不同的癌细胞。此外，iMacs_IL-12在人肺癌皮下或全身异种移植小鼠中表现出以T细胞依赖方式介导的强抗肿瘤作用。因此，我们提供了一种用于癌症治疗的即用型策略，以大规模生产GEMs。
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.
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