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 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 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.

中文翻译：

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Interleukin-21 工程通过 CEBPD 增强 NK 细胞对抗胶质母细胞瘤的活性


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）细胞是具有强抗肿瘤活性的先天免疫细胞，可能为 GBM 提供有前途的治疗策略。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，局部施用 IL-15 NK 细胞被证明有毒且在肿瘤控制方面无效。 IL-21 NK 细胞表现出独特的染色质可及性特征，其中 CCAAT/增强子结合蛋白 (C/EBP)，尤其是 CEBPD，作为调节其增强功能的关键转录因子。 IL-21 的缺失导致 NK 细胞效力丧失，而其过度表达则增加 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，增强其针对GBM的抗肿瘤功效。