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@ARTICLE{Hofman:291446,
      author       = {T. Hofman and S. W. Ng$^*$ and I. Garcés-Lázaro and F.
                      Heigwer$^*$ and M. Boutros$^*$ and A. Cerwenka},
      title        = {{IFN}γ mediates the resistance of tumor cells to distinct
                      {NK} cell subsets.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {12},
      number       = {7},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2024-01409},
      pages        = {e009410},
      year         = {2024},
      abstract     = {Immune checkpoint blockade targeting the adaptive immune
                      system has revolutionized the treatment of cancer. Despite
                      impressive clinical benefits observed, patient subgroups
                      remain non-responsive underscoring the necessity for
                      combinational therapies harnessing additional immune cells.
                      Natural killer (NK) cells are emerging tools for cancer
                      therapy. However, only subpopulations of NK cells that are
                      differentially controlled by inhibitory receptors exert
                      reactivity against particular cancer types. How to leverage
                      the complete anti-tumor potential of all NK cell subsets
                      without favoring the emergence of NK cell-resistant tumor
                      cells remains unresolved.We performed a genome-wide
                      CRISPR/Cas9 knockout resistance screen in melanoma cells in
                      co-cultures with human primary NK cells. We comprehensively
                      evaluated factors regulating tumor resistance and
                      susceptibility by focusing on NK cell subsets in an
                      allogenic setting. Moreover, we tested therapeutic blocking
                      antibodies currently used in clinical trials.Melanoma cells
                      deficient in antigen-presenting or the IFNγ-signaling
                      pathways were depleted in remaining NK cell-co-cultured
                      melanoma cells and displayed enhanced sensitivity to NK
                      cells. Treatment with IFNγ induced potent resistance of
                      melanoma cells to resting, IL-2-cultured and ADCC-activated
                      NK cells that depended on B2M required for the expression of
                      both classical and non-classical MHC-I. IFNγ-induced
                      expression of HLA-E mediated the resistance of melanoma
                      cells to the NKG2A+ KIR- and partially to the NKG2A+ KIR+ NK
                      cell subset. The expression of classical MHC-I by itself was
                      sufficient for the inhibition of the NKG2A- KIR+, but not
                      the NKG2A+ KIR+ NK cell subset. Treatment of NK cells with
                      monalizumab, an NKG2A blocking mAb, enhanced the reactivity
                      of a corresponding subset of NK cells. The combination of
                      monalizumab with lirilumab, blocking KIR2 receptors,
                      together with DX9, blocking KIR3DL1, was required to restore
                      cytotoxicity of all NK cell subsets against IFNγ-induced
                      resistant tumor cells in melanoma and tumors of different
                      origins.Our data reveal that in the context of NK cells,
                      IFNγ induces the resistance of tumor cells by the
                      upregulation of classical and non-classical MHC-I. Moreover,
                      we reveal insights into NK cell subset reactivity and
                      propose a therapeutic strategy involving combinational
                      monalizumab/lirilumab/DX9 treatment to fully restore the
                      antitumor response across NK cell subsets.},
      keywords     = {Humans / Killer Cells, Natural: immunology / Killer Cells,
                      Natural: metabolism / Interferon-gamma: metabolism /
                      Melanoma: immunology / Melanoma: drug therapy / Cell Line,
                      Tumor / Coculture Techniques / Immune Checkpoint Inhibitor
                      (Other) / Immunotherapy (Other) / Natural killer - NK
                      (Other) / Interferon-gamma (NLM Chemicals)},
      cin          = {B110},
      ddc          = {610},
      cid          = {I:(DE-He78)B110-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38955423},
      doi          = {10.1136/jitc-2024-009410},
      url          = {https://inrepo02.dkfz.de/record/291446},
}