In cocultures of glioblastoma stem cells and in PDX mouse models of glioblastoma, Shanley et al. showed that arming NK cells with IL-21 was safe and induced long-term antitumor activity, while arming NK cells with IL-15 was more toxic and less effective. IL-21 autocrine signaling induced STAT1 and STAT3 signaling and subsequent epigenetic reprogramming towards a unique chromatin accessibility signature that favored C/EBP TF family members – particularly CEBPD. Deletion of CEBPD resulted in loss of IL-21-mediated antitumor activity in NK cells, while overexpression of CEBPD enhanced IL-21-mediated metabolic fitness and long-term cytotoxicity.
Contributed by Lauren Hitchings
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.
Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (2) Department of Stem Cell Transp
Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (2) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (3) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (4) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (5) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (6) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (7) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (8) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (9) Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (10) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (11) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (12) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (13) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (14) Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (15) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (16) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (17) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (18) Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (19) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (20) Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (21) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (22) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (23) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (24) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (25) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (26) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (27) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (28) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (29) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (30) Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (31) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (32) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (33) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. (34) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. Electronic address: krezvani@mdanderson.org.
