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@ARTICLE{Rafei:301770,
      author       = {H. Rafei and R. Basar and S. Acharya and Y.-S. Hsu and P.
                      Liu and D. Zhang and T. Bohn$^*$ and Q. Liang and V. Mohanty
                      and R. Upadhyay and P. Li and P. Phadatare and M. Dede and
                      D. Xiong and H. Fan and C. M. Jones and S. Kunz and M. Daher
                      and A. K. Nunez Cortes and M. Shanley and B. Liu and S. M.
                      Moseley and C. Zhang and D. Fang and P. Banerjee and N.
                      Uprety and Y. Li and R. Shrestha and X. Wan and H. Shen and
                      V. Woods and A. L. Gilbert and S. Rawal and J. Dou and Y.
                      Tan and J.-M. Park and F. Reyes Silva and A. Biederstädt
                      and M. Kaplan and X. R. Jiang and I. Biederstädt and B.
                      Kumar and S. Tiberti and M. Moore and J. Jin and R. Z. Yang
                      and L. Muniz-Feliciano and S. Rosemore and P. Lin and G. M.
                      Deyter and N. W. Fowlkes and A. K. Jain and D. Marin and A.
                      Maitra and K. Chen and T. Bopp$^*$ and E. J. Shpall and K.
                      Rezvani},
      title        = {{CREM} is a regulatory checkpoint of {CAR} and {IL}-15
                      signalling in {NK} cells.},
      journal      = {Nature},
      volume       = {643},
      number       = {8073},
      issn         = {0028-0836},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2025-01150},
      pages        = {1076-1086},
      year         = {2025},
      note         = {2025 Jul;643(8073):1076-1086},
      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.},
      cin          = {FM01},
      ddc          = {500},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40468083},
      doi          = {10.1038/s41586-025-09087-8},
      url          = {https://inrepo02.dkfz.de/record/301770},
}