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@ARTICLE{Sun:300317,
      author       = {Q. Sun$^*$ and N. Wang$^*$ and J. Poelchen$^*$ and M.
                      Peter$^*$ and D. Novak$^*$ and F. G. Özbay Kurt$^*$ and R.
                      Bitsch$^*$ and H. Wu$^*$ and Y. Wang$^*$ and S. Pardo$^*$
                      and R. Han and S. Liu and L. Gong and Y. Zhang$^*$ and K.
                      Wistuba-Hamprecht$^*$ and V. Umansky$^*$ and J. Utikal$^*$},
      title        = {{N}eural crest-associated gene {FOXD}1 induces an
                      immunosuppressive microenvironment by regulating
                      myeloid-derived suppressor cells in melanoma.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {13},
      number       = {4},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2025-00763},
      pages        = {e010352},
      year         = {2025},
      note         = {#EA:A370#LA:A370#},
      abstract     = {Neural crest-associated genes play pivotal roles in tumor
                      initiation, progression, and the intricate dynamics of the
                      tumor microenvironment (TME). Myeloid-derived suppressor
                      cells (MDSC) within the TME are important in dampening T
                      cell activity and contributing to resistance against
                      immunotherapeutic interventions. The neural crest-associated
                      gene Forkhead Box D1 (FOXD1) has been identified as an
                      oncogenic factor that induces melanoma dedifferentiation and
                      progression. However, the underlying mechanisms and the
                      impact of FOXD1 on the antitumor immune response remain
                      unclear.To investigate the impacts of FOXD1 on the melanoma
                      microenvironment, we analyzed publicly available datasets
                      from multiple platforms, including TNMplot, TIMER2.0, etc.
                      In addition, FOXD1 was overexpressed (OE) or knocked down in
                      melanoma cells to identify its biological functions in vitro
                      and in vivo. Flow cytometry and arginase activity assay were
                      used to analyze the phenotype and function of MDSC. Western
                      blot, reverse transcription-PCR, or ELISA assays were
                      employed to analyze the expression of FOXD1 and its
                      downstream effectors. In vivo experiments were conducted to
                      investigate the role of FOXD1 in melanoma progression and
                      the influence on MDSC accumulation within the TME.We
                      demonstrate that increased FOXD1 levels inversely correlated
                      with melanoma responsiveness to immunotherapy. Ex-vivo
                      analyses unveiled that monocytes, exposed to conditioned
                      medium from FOXD1-OE melanoma cells, effectively suppressed
                      T cell proliferation and upregulated the expression of
                      programmed death-ligand 1 (PD-L1) and other
                      immunosuppressive factors. FOXD1 was identified as a direct
                      regulator of interleukin 6 (IL6) expression, which is
                      pivotal for MDSC induction. Blocking IL6 reversed
                      MDSC-associated immunosuppression. Additionally, miR-581, a
                      potential negative regulator of FOXD1, attenuated the impact
                      of FOXD1 on IL6 expression and MDSC differentiation. In vivo
                      experiments demonstrated that tumors derived from FOXD1 OE
                      melanoma cells contained a significantly higher frequency of
                      PD-L1+ MDSC compared with controls, while FOXD1 knockdown
                      resulted in reduced tumor growth and diminished MDSC
                      accumulation.Our study elucidated a novel function of FOXD1
                      in melanoma pathogenesis, highlighting its role in
                      orchestrating the immunosuppressive TME by promoting the
                      generation of MDSC via IL6 upregulation.},
      keywords     = {Myeloid-Derived Suppressor Cells: immunology /
                      Myeloid-Derived Suppressor Cells: metabolism / Melanoma:
                      genetics / Melanoma: pathology / Melanoma: immunology /
                      Melanoma: metabolism / Humans / Animals / Forkhead
                      Transcription Factors: metabolism / Forkhead Transcription
                      Factors: genetics / Tumor Microenvironment: immunology /
                      Mice / Neural Crest: metabolism / Cell Line, Tumor /
                      Immunosuppression (Other) / Myeloid-derived suppressor cell
                      - MDSC (Other) / Skin Cancer (Other) / Tumor
                      microenvironment - TME (Other) / Forkhead Transcription
                      Factors (NLM Chemicals) / FOXD1 protein, human (NLM
                      Chemicals)},
      cin          = {A370},
      ddc          = {610},
      cid          = {I:(DE-He78)A370-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40210238},
      doi          = {10.1136/jitc-2024-010352},
      url          = {https://inrepo02.dkfz.de/record/300317},
}