Interleukin-21 工程通过 CEBPD 增强 NK 细胞对抗胶质母细胞瘤的活性。
Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.
发表日期：2024 Aug 12
作者：
Mayra Shanley, May Daher, Jinzhuang Dou, Sufang Li, Rafet Basar, Hind Rafei, Merve Dede, Joy Gumin, Jezreel Pantaleόn Garcίa, Ana Karen Nunez Cortes, Shan He, Corry M Jones, Sunil Acharya, Natalie W Fowlkes, Donghai Xiong, Sanjay Singh, Hila Shaim, Samantha Claire Hicks, Bin Liu, Abhinav Jain, Mohammad Fayyad Zaman, Qi Miao, Ye Li, Nadima Uprety, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Vakul Mohanty, Patrick Zhang, Scott E Evans, Elizabeth J Shpall, Frederick F Lang, Ken Chen, Katayoun Rezvani
来源：
CANCER CELL
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。使用多个体内模型，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，局部区域施用的 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。 CEBPD 的缺失导致 IL-21 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。版权所有 © 2024 Elsevier Inc. 保留所有权利。
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.Copyright © 2024 Elsevier Inc. All rights reserved.