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@ARTICLE{Linder:301275,
      author       = {A. Linder and D. Nixdorf and N. Kuhl and I. Piseddu and T.
                      Xu and A. V. Holtermann and G. Kuut and R. Endres and N.
                      Philipp and V. Bücklein and J. de Graaff and T. Carell and
                      S. Kobold and R. Kischel and V. Hornung and M. Subklewe$^*$},
      title        = {{STING} activation improves {T}-cell-engaging immunotherapy
                      for acute myeloid leukemia.},
      journal      = {Blood},
      volume       = {145},
      number       = {19},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2025-00960},
      pages        = {2149 - 2160},
      year         = {2025},
      abstract     = {T-cell-recruiting bispecific antibodies (BsAbs) are in
                      clinical development for relapsed/refractory acute myeloid
                      leukemia (AML). Despite promising results, early clinical
                      trials have failed to demonstrate durable responses. We
                      investigated whether activation of the innate immune system
                      through stimulator of interferon (IFN) genes (STING) can
                      enhance target cell killing by a BsAb targeting CD33 (CD33
                      bispecific T-cell engager molecule; AMG 330). Indeed, we
                      show that cytotoxicity against AML mediated by AMG 330 can
                      be greatly enhanced when combined with the STING agonist
                      2',3'-cyclic guanosine monophosphate-adenosine monophosphate
                      (cGAMP) or diamidobenzimidazole (diABZI). We used in vitro
                      cytotoxicity assays, immunoblotting, transcriptomic
                      analyses, and extensive CRISPR-Cas9 knockout experiments to
                      investigate the enhancing effect of a STING agonist on the
                      cytotoxicity of AMG 330 against AML. Importantly, we
                      validated our findings with primary AML cells and in a
                      xenograft AML model. Mechanistically, in addition to direct
                      cytotoxic effects of STING activation on AML cells,
                      activated T cells render AML cells more susceptible to STING
                      activation through their effector cytokines, IFN-γ and
                      tumor necrosis factor, resulting in enhanced type I IFN
                      production and induction of IFN-stimulated genes. This feeds
                      back to the T cells, leading to a further increase in
                      effector cytokines and an overall cytotoxic T-cell
                      phenotype, contributing to the beneficial effect of
                      cGAMP/diABZI in enhancing AMG 330-mediated lysis. We
                      established a key role for IFN-γ in AMG 330-mediated
                      cytotoxicity against AML cells and in rendering AML cells
                      responsive to STING agonism. Here, we propose to improve the
                      efficacy of CD33-targeting BsAbs by combining them with a
                      STING agonist.},
      keywords     = {Leukemia, Myeloid, Acute: immunology / Leukemia, Myeloid,
                      Acute: therapy / Leukemia, Myeloid, Acute: pathology /
                      Humans / Membrane Proteins: agonists / Membrane Proteins:
                      immunology / Membrane Proteins: genetics / Membrane
                      Proteins: metabolism / Animals / Mice / Immunotherapy:
                      methods / T-Lymphocytes: immunology / Antibodies,
                      Bispecific: pharmacology / Antibodies, Bispecific:
                      therapeutic use / Nucleotides, Cyclic: pharmacology / Cell
                      Line, Tumor / Xenograft Model Antitumor Assays / Lymphocyte
                      Activation / Membrane Proteins (NLM Chemicals) / STING1
                      protein, human (NLM Chemicals) / Antibodies, Bispecific (NLM
                      Chemicals) / Nucleotides, Cyclic (NLM Chemicals) / cyclic
                      guanosine monophosphate-adenosine monophosphate (NLM
                      Chemicals)},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40009483},
      doi          = {10.1182/blood.2024026934},
      url          = {https://inrepo02.dkfz.de/record/301275},
}