{Reference Type}: Journal Article
{Title}: Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.
{Author}: Shanley M;Daher M;Dou J;Li S;Basar R;Rafei H;Dede M;Gumin J;Pantaleόn Garcίa J;Nunez Cortes AK;He S;Jones CM;Acharya S;Fowlkes NW;Xiong D;Singh S;Shaim H;Hicks SC;Liu B;Jain A;Zaman MF;Miao Q;Li Y;Uprety N;Liu E;Muniz-Feliciano L;Deyter GM;Mohanty V;Zhang P;Evans SE;Shpall EJ;Lang FF;Chen K;Rezvani K;
{Journal}: Cancer Cell
{Volume}: 42
{Issue}: 8
{Year}: 2024 Aug 12
{Factor}: 38.585
{DOI}: 10.1016/j.ccell.2024.07.007
{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.