肿瘤细胞治疗研究
英文原题：Developing enhanced immunotherapy using NKG2A knockout human pluripotent stem cell-derived NK cells.
肿瘤免疫治疗正受到越来越多的关注。
癌症免疫治疗正受到越来越多的关注。然而，免疫检查点被癌细胞利用以逃逸抗肿瘤免疫治疗。在此，我们在人类多能干细胞（hPSCs）中敲除了NKG2A——一种表达于自然杀伤（NK）细胞上的免疫检查点，并将这些hPSCs分化为NK（PSC-NK）细胞。我们发现，NKG2A敲除（KO）增强了PSC-NK细胞的抗肿瘤和抗病毒能力。NKG2A KO使PSC-NK细胞在体外对表达HLA-E的胶质母细胞瘤（GBM）细胞、白血病细胞以及严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的细胞具有更高的细胞毒性。NKG2A KO PSC-NK细胞在体内也发挥了强效的抗肿瘤活性，在异种移植GBM小鼠模型中显著抑制了肿瘤进展并延长了荷瘤小鼠的生存期。这些发现凸显了具有免疫检查点KO的PSC-NK细胞作为一种有前景的细胞免疫疗法的潜力。hPSCs的无限供应和易于基因工程改造的特点，使基因工程改造的PSC-NK成为易于获取的“现货型”癌症免疫治疗的一个有吸引力的选择。
Cancer immunotherapy is gaining increasing attention. However, immune checkpoints are exploited by cancer cells to evade anti-tumor immunotherapy. Here, we knocked out NKG2A, an immune checkpoint expressed on natural killer (NK) cells, in human pluripotent stem cells (hPSCs) and differentiated these hPSCs into NK (PSC-NK) cells. We show that NKG2A knockout (KO) enhances the anti-tumor and anti-viral capabilities of PSC-NK cells. NKG2A KO endows PSC-NK cells with higher cytotoxicity against HLA-E-expressing glioblastoma (GBM) cells, leukemia cells, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells in vitro. The NKG2A KO PSC-NK cells also exerted potent anti-tumor activity in vivo, leading to substantially suppressed tumor progression and prolonged survival of tumor-bearing mice in a xenograft GBM mouse model. These findings underscore the potential of PSC-NK cells with immune checkpoint KO as a promising cell-based immunotherapy. The unlimited supply and ease of genetic engineering of hPSCs makes genetically engineered PSC-NK an attractive option for easily accessible "off-the-shelf" cancer immunotherapy.
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