Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101130617 Publication Model: Print Cited Medium: Internet ISSN: 1878-3686 (Electronic) Linking ISSN: 15356108 NLM ISO Abbreviation: Cancer Cell Subsets: MEDLINE
    • Publication Information:
      Original Publication: Cambridge, Mass. : Cell Press, c2002-
    • Subject Terms:
      Killer Cells, Natural*/immunology ; Killer Cells, Natural*/metabolism ; Glioblastoma*/immunology ; Glioblastoma*/genetics ; Glioblastoma*/pathology ; Glioblastoma*/therapy ; Interleukins*/genetics ; Interleukins*/metabolism ; Interleukins*/immunology ; CCAAT-Enhancer-Binding Protein-delta*/metabolism ; CCAAT-Enhancer-Binding Protein-delta*/genetics ; Brain Neoplasms*/immunology ; Brain Neoplasms*/genetics ; Brain Neoplasms*/pathology ; Brain Neoplasms*/therapy; Humans ; Animals ; Mice ; Cell Line, Tumor ; Interleukin-15/genetics ; Interleukin-15/metabolism ; Interleukin-15/immunology ; Xenograft Model Antitumor Assays
    • Abstract:
      Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.
      Competing Interests: Declaration of interests M.S., M. Daher, R.B., H.R., S.A., Y.L., N.U., E.L., E.J.S., K.R., and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical. R.B., E.J.S., K.R., and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Affimed GmbH. K.R. participates on the Scientific Advisory Board for Avenge Bio, Virogin Biotech, Navan Technologies, Caribou Biosciences, Bit Bio Limited, Replay Holdings, oNKo Innate, and The Alliance for Cancer Gene Therapy ACGT. K.R. is the Scientific founder of Syena. E.J.S. has served on the Scientific Advisory Board for Adaptimmune, Axio, Celaid, FibroBiologics, Navan Technologies, New York Blood Center and Novartis. M Daher participates on the Scientific Advisory Board for Cellsbin. M.S., H.S., E.J.S., and K.R. have filed for a patent (20230074303); “Cell immunotherapy for the treatment of cancer.”
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
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    • Grant Information:
      P30 CA016672 United States CA NCI NIH HHS; U01 CA247760 United States CA NCI NIH HHS; S10 OD024977 United States OD NIH HHS; R35 HL144805 United States HL NHLBI NIH HHS; P50 CA127001 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: CEBPD; GBM; IL-21; NK cells
    • Accession Number:
      MKM3CA6LT1 (interleukin-21)
      0 (Interleukins)
      142662-43-9 (CCAAT-Enhancer-Binding Protein-delta)
      0 (Interleukin-15)
    • Publication Date:
      Date Created: 20240813 Date Completed: 20240813 Latest Revision: 20240904
    • Publication Date:
      20240904
    • Accession Number:
      PMC11370652
    • Accession Number:
      10.1016/j.ccell.2024.07.007
    • Accession Number:
      39137729