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, Biederstädt Alexander, Kaplan Mecit, Jiang Xin Ru, Biederstädt 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
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nature. 2025 Jun 4. doi: 10.1038/s41586-025-09087-8.
Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer. 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.
嵌合抗原受体（CAR）自然杀伤（NK）细胞免疫疗法为抗癌提供了一种很有前景的方法。然而，调节CAR-NK细胞活性的分子机制仍不清楚。在这里，我们确定转录因子环磷酸腺苷反应元件调节因子（CREM）是NK细胞功能的关键调节因子。转录组分析显示，在肿瘤小鼠模型中过继转移后效应功能达到峰值时，CAR-NK细胞中的CREM显著诱导，且该峰值与激活和功能障碍的特征一致。我们证明，CAR激活和白细胞介素-15信号传导均可迅速诱导NK细胞中CREM上调。在功能上，CREM缺失增强了CAR-NK细胞在体外和体内的效应功能，并增加了再次攻击后对肿瘤诱导的免疫抑制的抗性。在机制上，我们确定CREM的诱导是由PKA-CREB信号通路介导的，该信号通路可通过CAR激活下游的基于免疫受体酪氨酸的激活基序信号或白细胞介素-15激活。最后，我们的研究结果表明，CREM通过对CAR-NK细胞进行表观遗传重编程来发挥其调节功能。我们的结果为将CREM作为增强CAR-NK细胞抗肿瘤疗效的治疗靶点提供了支持。
