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@ARTICLE{Conche:212536,
      author       = {C. Conche and F. Finkelmeier and M. Pešić and A. M.
                      Nicolas and T. W. Böttger and K. B. Kennel and D. Denk and
                      F. Ceteci and K. Mohs and E. Engel and Ö. Canli and Y.
                      Dabiri and K.-H. Peiffer and S. Zeuzem and G. Salinas and T.
                      Longerich and H. Yang and F. R. Greten$^*$},
      title        = {{C}ombining ferroptosis induction with {MDSC} blockade
                      renders primary tumours and metastases in liver sensitive to
                      immune checkpoint blockade.},
      journal      = {Gut},
      volume       = {72},
      number       = {9},
      issn         = {0017-5749},
      address      = {London},
      publisher    = {BMJ Publishing Group},
      reportid     = {DKFZ-2023-00221},
      pages        = {1774-1782},
      year         = {2023},
      note         = {2023 Sep;72(9):1774-1782},
      abstract     = {Investigating the effect of ferroptosis in the tumour
                      microenvironment to identify combinatory therapy for liver
                      cancer treatment.Glutathione peroxidase 4 (GPx4), which is
                      considered the master regulator of ferroptosis, was
                      genetically altered in murine models for hepatocellular
                      carcinoma (HCC) and colorectal cancer (CRC) to analyse the
                      effect of ferroptosis on tumour cells and the immune tumour
                      microenvironment. The findings served as foundation for the
                      identification of additional targets for combine therapy
                      with ferroptotic inducer in the treatment of HCC and liver
                      metastasis.Surprisingly, hepatocyte-restricted GPx4 loss
                      does not suppress hepatocellular tumourigenesis. Instead,
                      GPx4-associated ferroptotic hepatocyte death causes a tumour
                      suppressive immune response characterised by a
                      CXCL10-dependent infiltration of cytotoxic CD8+ T cells that
                      is counterbalanced by PD-L1 upregulation on tumour cells as
                      well as by a marked HMGB1-mediated myeloid derived
                      suppressor cell (MDSC) infiltration. Blocking PD-1 or HMGB1
                      unleashes T cell activation and prolongs survival of mice
                      with Gpx4-deficient liver tumours. A triple combination of
                      the ferroptosis inducing natural compound withaferin A, the
                      CXCR2 inhibitor SB225002 and α-PD-1 greatly improves
                      survival of wild-type mice with liver tumours. In contrast,
                      the same combination does not affect tumour growth of
                      subcutaneously grown CRC organoids, while it decreases their
                      metastatic growth in liver.Our data highlight a
                      context-specific ferroptosis-induced immune response that
                      could be therapeutically exploited for the treatment of
                      primary liver tumours and liver metastases.},
      keywords     = {adenocarcinoma (Other) / cell death (Other) / colorectal
                      cancer (Other) / immunotherapy (Other) / liver (Other)},
      cin          = {FM01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36707233},
      doi          = {10.1136/gutjnl-2022-327909},
      url          = {https://inrepo02.dkfz.de/record/212536},
}