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@ARTICLE{Fermi:282718,
      author       = {V. Fermi and R. Warta and A. Wöllner and C. Lotsch and L.
                      Jassowicz$^*$ and C. Rapp and M. Knoll$^*$ and G. Jungwirth
                      and C. Jungk and P. Dao Trong and A. von Deimling$^*$ and A.
                      Abdollahi$^*$ and A. Unterberg and C. Herold-Mende},
      title        = {{E}ffective reprogramming of patient-derived {M}2-polarized
                      glioblastoma-associated microglia/macrophages by treatment
                      with {GW}2580.},
      journal      = {Clinical cancer research},
      volume       = {29},
      number       = {22},
      issn         = {1078-0432},
      address      = {Philadelphia, Pa. [u.a.]},
      publisher    = {AACR},
      reportid     = {DKFZ-2023-01844},
      pages        = {4685-4697},
      year         = {2023},
      note         = {2023 Nov 14;29(22):4685-4697},
      abstract     = {Targeting immunosuppressive and pro-tumorigenic
                      glioblastoma-associated macrophages and microglial cells
                      (GAMs) has great potential to improve patient outcomes.
                      Colony stimulating factor-1 receptor (CSF1R) has emerged as
                      a promising target for reprograming anti-inflammatory
                      M2-like GAMs. However, treatment data on patient-derived,
                      tumor-educated GAMs and their influence on the adaptive
                      immunity are lacking.CD11b+-GAMs freshly isolated from
                      patient tumors were treated with CSF1R-targeting drugs
                      PLX3397, BLZ945, and GW2580. Phenotypical changes upon
                      treatment were assessed using RNAseq, flow cytometry, and
                      cytokine quantification. Functional analyses included iNOS
                      activity, phagocytosis, transmigration, and autologous tumor
                      cell killing assays. Antitumor effects and changes in GAM
                      activation were confirmed in a complex patient-derived 3D
                      tumor organoid model serving as a tumor avatar.The most
                      effective reprogramming of GAMs was observed upon GW2580
                      treatment, which led to the downregulation of M2-related
                      markers, IL-6, and IL-10, ERK1/2 and MAPK signaling
                      pathways, while M1-like markers, gene set enrichment
                      indicating activated MHC-II presentation, phagocytosis, and
                      T-cell killing were substantially increased. Moreover,
                      treatment of patient-derived glioblastoma organoids with
                      GW2580 confirmed successful reprogramming, resulting in
                      impaired tumor cell proliferation. In line with its failure
                      in clinical trials, PLX3397 was ineffective in our
                      analysis.This comparative analysis of CSF1R-targeting drugs
                      on patient-derived GAMs and human glioblastoma avatars
                      identified GW2580 as the most powerful inhibitor with the
                      ability to polarize immunosuppressive GAMs to a
                      proinflammatory phenotype, supporting antitumor T cell
                      responses while also exerting a direct antitumor effect.
                      These data indicate that GW2580 could be an important pillar
                      in future therapies for glioblastoma.},
      cin          = {B060 / E210 / B300 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B060-20160331 / I:(DE-He78)E210-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37682326},
      doi          = {10.1158/1078-0432.CCR-23-0576},
      url          = {https://inrepo02.dkfz.de/record/282718},
}