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@ARTICLE{Kober:285390,
      author       = {C. Kober$^*$ and J. Roewe$^*$ and N. Schmees and L. Roese
                      and U. Roehn and B. Bader and D. Stoeckigt and F. Prinz and
                      M. Gorjánácz and H. G. Roider and C. Olesch$^*$ and G.
                      Leder and H. Irlbacher and R. Lesche and J. Lefranc and M.
                      Oezcan-Wahlbrink$^*$ and A. S. Batra$^*$ and N. Elmadany$^*$
                      and R. Carretero$^*$ and K. Sahm$^*$ and I. Oezen$^*$ and F.
                      Cichon$^*$ and D. Baumann$^*$ and A. Sadik$^*$ and C. A.
                      Opitz$^*$ and H. Weinmann and I. V. Hartung and B. Kreft and
                      R. Offringa$^*$ and M. Platten$^*$ and I. Gutcher},
      title        = {{T}argeting the aryl hydrocarbon receptor ({A}h{R}) with
                      {BAY} 2416964: a selective small molecule inhibitor for
                      cancer immunotherapy.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {11},
      number       = {11},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2023-02357},
      pages        = {e007495},
      year         = {2023},
      note         = {#EA:D220# / EA#D200},
      abstract     = {The metabolism of tryptophan to kynurenines (KYN) by
                      indoleamine-2,3-dioxygenase or tryptophan-2,3-dioxygenase is
                      a key pathway of constitutive and adaptive tumor immune
                      resistance. The immunosuppressive effects of KYN in the
                      tumor microenvironment are predominantly mediated by the
                      aryl hydrocarbon receptor (AhR), a cytosolic transcription
                      factor that broadly suppresses immune cell function.
                      Inhibition of AhR thus offers an antitumor therapy
                      opportunity via restoration of immune system functions.The
                      expression of AhR was evaluated in tissue microarrays of
                      head and neck squamous cell carcinoma (HNSCC), non-small
                      cell lung cancer (NSCLC) and colorectal cancer (CRC). A
                      structure class of inhibitors that block AhR activation by
                      exogenous and endogenous ligands was identified, and further
                      optimized, using a cellular screening cascade. The
                      antagonistic properties of the selected AhR inhibitor
                      candidate BAY 2416964 were determined using transactivation
                      assays. Nuclear translocation, target engagement and the
                      effect of BAY 2416964 on agonist-induced AhR activation were
                      assessed in human and mouse cancer cells. The
                      immunostimulatory properties on gene and cytokine expression
                      were examined in human immune cell subsets. The in vivo
                      efficacy of BAY 2416964 was tested in the syngeneic
                      ovalbumin-expressing B16F10 melanoma model in mice.
                      Coculture of human H1299 NSCLC cells, primary peripheral
                      blood mononuclear cells and fibroblasts mimicking the human
                      stromal-tumor microenvironment was used to assess the
                      effects of AhR inhibition on human immune cells.
                      Furthermore, tumor spheroids cocultured with tumor
                      antigen-specific MART-1 T cells were used to study the
                      antigen-specific cytotoxic T cell responses. The data were
                      analyzed statistically using linear models.AhR expression
                      was observed in tumor cells and tumor-infiltrating immune
                      cells in HNSCC, NSCLC and CRC. BAY 2416964 potently and
                      selectively inhibited AhR activation induced by either
                      exogenous or endogenous AhR ligands. In vitro, BAY 2416964
                      restored immune cell function in human and mouse cells, and
                      furthermore enhanced antigen-specific cytotoxic T cell
                      responses and killing of tumor spheroids. In vivo, oral
                      application with BAY 2416964 was well tolerated, induced a
                      proinflammatory tumor microenvironment, and demonstrated
                      antitumor efficacy in a syngeneic cancer model in mice.These
                      findings identify AhR inhibition as a novel therapeutic
                      approach to overcome immune resistance in various types of
                      cancers.},
      keywords     = {Drug Evaluation, Preclinical (Other) / Immune Checkpoint
                      Inhibitors (Other) / Immunotherapy (Other) /
                      Indoleamine-Pyrrole 2,3,-Dioxygenase (Other) / Metabolic
                      Networks and Pathways (Other)},
      cin          = {D200 / D220 / D170 / HD01 / B350},
      ddc          = {610},
      cid          = {I:(DE-He78)D200-20160331 / I:(DE-He78)D220-20160331 /
                      I:(DE-He78)D170-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B350-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37963637},
      doi          = {10.1136/jitc-2023-007495},
      url          = {https://inrepo02.dkfz.de/record/285390},
}