PDF(Pubmed)
Abstract：
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.
摘要：
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）细胞是先天性免疫细胞，具有很强的抗肿瘤活性，可能为GBM提供有希望的治疗策略。我们比较了经工程改造以表达白介素(IL)-15或IL-21的NK细胞的抗GBM活性。使用多个体内模型，IL-21NK细胞在安全性和长期抗肿瘤活性方面均优于IL-15NK细胞，局部给药的IL-15NK细胞在肿瘤控制中证明毒性和无效。IL-21NK细胞表现出独特的染色质可及性特征，与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。CEBPD的缺失导致IL-21NK细胞效力的丧失,而其过度表达增加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，增强它们对GBM的抗肿瘤功效。
