TY  - JOUR
AU  - Rafei, Hind
AU  - Basar, Rafet
AU  - Acharya, Sunil
AU  - Hsu, Yu-Sung
AU  - Liu, Pinghua
AU  - Zhang, Deqiang
AU  - Bohn, Toszka
AU  - Liang, Qingnan
AU  - Mohanty, Vakul
AU  - Upadhyay, Ranjan
AU  - Li, Ping
AU  - Phadatare, Pravin
AU  - Dede, Merve
AU  - Xiong, Donghai
AU  - Fan, Huihui
AU  - Jones, Corry Mathew
AU  - Kunz, Sebastian
AU  - Daher, May
AU  - Nunez Cortes, Ana Karen
AU  - Shanley, Mayra
AU  - Liu, Bin
AU  - Moseley, Sadie Mae
AU  - Zhang, Chenyu
AU  - Fang, Dexing
AU  - Banerjee, Pinaki
AU  - Uprety, Nadima
AU  - Li, Ye
AU  - Shrestha, Rejeena
AU  - Wan, Xinhai
AU  - Shen, Hong
AU  - Woods, Vernikka
AU  - Gilbert, April Lamour
AU  - Rawal, Seema
AU  - Dou, Jinzhuang
AU  - Tan, Yukun
AU  - Park, Jeong-Min
AU  - Reyes Silva, Francia
AU  - Biederstädt, Alexander
AU  - Kaplan, Mecit
AU  - Jiang, Xin Ru
AU  - Biederstädt, Inci
AU  - Kumar, Bijender
AU  - Tiberti, Silvia
AU  - Moore, Madison
AU  - Jin, Jingling
AU  - Yang, Ryan Z
AU  - Muniz-Feliciano, Luis
AU  - Rosemore, Samuel
AU  - Lin, Paul
AU  - Deyter, Gary M
AU  - Fowlkes, Natalie Wall
AU  - Jain, Abhinav K
AU  - Marin, David
AU  - Maitra, Anirban
AU  - Chen, Ken
AU  - Bopp, Tobias
AU  - Shpall, Elizabeth J
AU  - Rezvani, Katayoun
TI  - CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells.
JO  - Nature
VL  - 643
IS  - 8073
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2025-01150
SP  - 1076-1086
PY  - 2025
N1  - 2025 Jul;643(8073):1076-1086
AB  - Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1-3. However, the molecular mechanisms that regulate CAR-NK cell activity remain unclear. Here we identify the transcription factor cyclic AMP response element modulator (CREM) as a crucial regulator of NK cell function. Transcriptomic analysis revealed a significant induction of CREM in CAR-NK cells during the peak of effector function after adoptive transfer in a tumour mouse model, and this peak coincided with signatures of both activation and dysfunction. We demonstrate that both CAR activation and interleukin-15 signalling rapidly induce CREM upregulation in NK cells. Functionally, CREM deletion enhances CAR-NK cell effector function both in vitro and in vivo and increases resistance to tumour-induced immunosuppression after rechallenge. Mechanistically, we establish that induction of CREM is mediated by the PKA-CREB signalling pathway, which can be activated by immunoreceptor tyrosine-based activation motif signalling downstream of CAR activation or by interleukin-15. Finally, our findings reveal that CREM exerts its regulatory functions through epigenetic reprogramming of CAR-NK cells. Our results provide support for CREM as a therapeutic target to enhance the antitumour efficacy of CAR-NK cells.
LB  - PUB:(DE-HGF)16
C6  - pmid:40468083
DO  - DOI:10.1038/s41586-025-09087-8
UR  - https://inrepo02.dkfz.de/record/301770
ER  -