Journal Article

CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells

Phadatare, Pravin, Biederstädt, Alexander, Rawal, Seema, Liu, Bin, Jain, Abhinav K, Maitra, Anirban, Lin, Paul, Deyter, Gary M, Rezvani, Katayoun, Rosemore, Samuel, Yang, Ryan Z, Mohanty, Vakul, Zhang, Deqiang, Li, Ping, Kaplan, Mecit, Tiberti, Silvia, Basar, Rafet, Shen, Hong, Xiong, Donghai, Gilbert, April Lamour, Marin, David, Nunez Cortes, Ana Karen, Kumar, Bijender, Hsu, Yu-Sung, Li, Ye, Dede, Merve, Jin, Jingling, Fan, Huihui, Daher, May, Shanley, Mayra, Shrestha, Rejeena, Rafei, Hind, Wan, Xinhai, Acharya, Sunil, Shpall, Elizabeth J, Fang, Dexing, Park, Jeong-Min, Bopp, Tobias, Dou, Jinzhuang, Uprety, Nadima, Liu, Pinghua, Upadhyay, Ranjan, Moore, Madison, Fowlkes, Natalie Wall, Jones, Corry Mathew, Tan, Yukun, Woods, Vernikka, Biederstädt, Inci, Bohn, Toszka, Kunz, Sebastian, Jiang, Xin Ru, Moseley, Sadie Mae, Banerjee, Pinaki, Reyes Silva, Francia, Zhang, Chenyu, Liang, Qingnan, Chen, Ken, Muniz-Feliciano, Luis

2025

Overview

Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1, 2–3. 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.The transcription factor CREM is a pivotal regulator of NK cell function, making CREM a valuable target to increase the efficacy of anticancer immunotherapies based on this cell population and chimeric antigen receptors.

• Publisher: Nature Publishing Group
• Subject: Adoptive transfer / Anticancer properties / Antigens / Antitumor activity / Cell cycle / Chimeric antigen receptors / Clonal deletion / Cyclic AMP / Cyclic AMP response element modulator / Cyclic AMP response element-binding protein / Cytokines / Effectiveness / Epigenetics / Immunoreceptor tyrosine-based activation motif / Immunosuppression / Immunotherapy / Interleukin 15 / Interleukins / Molecular modelling / Natural killer cells / Protein kinase A / Receptors / Signal transduction / Therapeutic targets / Transcription factors / Transcriptomics / Tumors / Tyrosine / Variance analysis