Journal Article

DKFZ-2025-01150

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells.

Rafei, H. ; Basar, R. ; Acharya, S. ; Hsu, Y.-S. ; Liu, P. ; Zhang, D. ; Bohn, T.DKFZ* ; Liang, Q. ; Mohanty, V. ; Upadhyay, R. ; Li, P. ; Phadatare, P. ; Dede, M. ; Xiong, D. ; Fan, H. ; Jones, C. M. ; Kunz, S. ; Daher, M. ; Nunez Cortes, A. K. ; Shanley, M. ; Liu, B. ; Moseley, S. M. ; Zhang, C. ; Fang, D. ; Banerjee, P. ; Uprety, N. ; Li, Y. ; Shrestha, R. ; Wan, X. ; Shen, H. ; Woods, V. ; Gilbert, A. L. ; Rawal, S. ; Dou, J. ; Tan, Y. ; Park, J.-M. ; Reyes Silva, F. ; Biederstädt, A. ; Kaplan, M. ; Jiang, X. R. ; Biederstädt, I. ; Kumar, B. ; Tiberti, S. ; Moore, M. ; Jin, J. ; Yang, R. Z. ; Muniz-Feliciano, L. ; Rosemore, S. ; Lin, P. ; Deyter, G. M. ; Fowlkes, N. W. ; Jain, A. K. ; Marin, D. ; Maitra, A. ; Chen, K. ; Bopp, T.DKFZ* ; Shpall, E. J. ; Rezvani, K.

2025
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41586-025-09087-8

Abstract: 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.

Note: 2025 Jul;643(8073):1076-1086

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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