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

• 成果类型: Article
• 署名作者: Rafei, Hind; Basar, Rafet; Acharya, Sunil; Hsu, Yu-Sung; Liu, Pinghua; Zhang, Deqiang; Bohn, Toszka; Liang, Qingnan; Mohanty, Vakul; Upadhyay, Ranjan; Li, Ping; Phadatare, Pravin; Dede, Merve; Xiong, Donghai; Fan, Huihui; Jones, Corry Mathew; Kunz, Sebastian; Daher, May; Nunez Cortes, Ana Karen; Shanley, Mayra; Liu, Bin; Moseley, Sadie Mae; Zhang, Chenyu; Fang, Dexing; Banerjee, Pinaki; Uprety, Nadima; Li, Ye; Shrestha, Rejeena; Wan, Xinhai; Shen, Hong; Woods, Vernikka; Gilbert, April Lamour; Rawal, Seema; Dou, Jinzhuang; Tan, Yukun; Park, Jeong-Min; Reyes Silva, Francia; Biederstadt, Alexander; Kaplan, Mecit; Jiang, Xin Ru; Biederstadt, Inci; Kumar, Bijender; Tiberti, Silvia; Moore, Madison; Jin, Jingling; Yang, Ryan Z.; Muniz-Feliciano, Luis; Rosemore, Samuel; Lin, Paul; Deyter, Gary M.; Fowlkes, Natalie Wall; Jain, Abhinav K.; Marin, David; Maitra, Anirban; Chen, Ken; Bopp, Tobias; Shpall, Elizabeth J.; Rezvani, Katayoun
• 署名单位: University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Johannes Gutenberg University of Mainz; Johannes Gutenberg University of Mainz; Helmholtz Association; German Cancer Research Center (DKFZ); University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; University of Texas Health Science Center Houston; University of Texas System; UTMD Anderson Cancer Center; Technical University of Munich; University System of Maryland; University of Maryland College Park; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Johannes Gutenberg University of Mainz
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1973
• DOI: 10.1038/s41586-025-09087-8
• 发表日期: 2025-07-24
• 关键词: expression; gene; transcription; activation; binding; attenuation; suppression; icer

摘要

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.