Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Cancer Cell. 2024 Aug 12;42(8):1450-1466.e11. doi: 10.1016/j.ccell.2024.07.007.
Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.
胶质母细胞瘤（GBM）是一种侵袭性脑癌，治疗选择有限。自然杀伤（NK）细胞是先天免疫细胞，具有强大的抗肿瘤活性，可能为 GBM 提供一种有前途的治疗策略。我们比较了表达白细胞介素（IL）-15 或 IL-21 的 NK 细胞的抗 GBM 活性。使用多种体内模型，IL-21 NK 细胞在安全性和长期抗肿瘤活性方面均优于 IL-15 NK 细胞，局部给予的 IL-15 NK 细胞具有毒性且无法控制肿瘤。IL-21 NK 细胞显示出独特的染色质可及性特征，CCAAT/增强子结合蛋白（C/EBP），特别是 CEBPD，作为关键转录因子调节其增强功能。CEBPD 的缺失导致 IL-21 NK 细胞效力丧失，而过表达增加了 NK 细胞的长期细胞毒性和代谢适应性。这些结果表明，IL-21 通过 C/EBP 转录因子驱动 NK 细胞的表观遗传重编程，增强其对 GBM 的抗肿瘤功效。
