Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD

• DOI: 10.1016/j.ccell.2024.07.007
• Publication Date: 2024-08-12T14:34:06Z
• Authors: Mayra Shanley; May Daher; Jinzhuang Dou; Sufang Li; Rafet Basar; Hind Rafei; Merve Dede; Joy Gumin; Jezreel Pantaleόn...; Ana Karen Nunez C...; Shan He; Corry M. Jones; Sunil Acharya; Natalie W. Fowlkes; Donghai Xiong; Sanjay Singh; Hila Shaim; Samantha Claire H...; Bin Liu; Abhinav Jain; Mohammad Fayyad Z...; 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
• Keywords: Reprogramming; Interleukin 15

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM of NK engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 were superior IL-15 both terms safety long-term activity, locoregionally administered proving toxic ineffective at tumor control. displayed unique chromatin accessibility signature, CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion CEBPD resulted loss cell potency while its overexpression increased cytotoxicity metabolic fitness. These results suggest that IL-21, through C/EBP factors, drives epigenetic reprogramming cells, enhancing efficacy against