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@ARTICLE{Sax:301262,
      author       = {A. Sax and P. May and S. Enssle and N. Soliman and T.
                      Nedelko and G. Mandracci and F. Stögbauer and L. Joachim
                      and C. Winter$^*$ and F. Bassermann$^*$ and K. Steiger and
                      N. El Khawanky and H. Poeck and S. Heidegger},
      title        = {{D}efects in the necroptosis machinery are a cancer
                      resistance mechanism to checkpoint inhibitor immunotherapy.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {13},
      number       = {5},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2025-00947},
      pages        = {e010433},
      year         = {2025},
      abstract     = {Immune checkpoint inhibitors (ICIs) of programmed cell
                      death protein-1 (PD-1) or cytotoxic T-lymphocytes-associated
                      protein 4 (CTLA-4) reinvigorate strong polyclonal T-cell
                      immune responses against tumor cells. For many patients,
                      these therapies fail because the development of spontaneous
                      immune responses is often compromised, as the tumor
                      microenvironment (TME) lacks proinflammatory signals
                      resulting in suboptimal activation of antigen-presenting
                      cells (APCs). Necroptosis is a special form of programmed
                      cell death associated with leakage of inflammatory factors
                      that can lead to APC maturation. However, it is unclear to
                      which extent functional necroptosis in tumor cells
                      contributes to ICI immunotherapy.With genetically engineered
                      tumor cell lines that lack specific components of the
                      necroptosis machinery (mixed lineage kinase domain-like
                      pseudokinase (MLKL), receptor interacting protein kinase 3
                      (RIPK3)), we addressed the importance of necroptotic tumor
                      cell death for the efficacy of ICI immunotherapy in murine
                      models. Preclinical data were aligned with genome-wide
                      transcriptional programs in patient tumor samples at
                      diagnosis and during ICI treatment for the activity of these
                      pathways and association with treatment outcome.Mice bearing
                      MLKL-deficient or RIPK3-deficient tumors failed to control
                      tumor growth in response to anti-PD-1/anti-CTLA-4
                      immunotherapy. Mechanistically, defects in the necroptosis
                      pathway resulted in reduced tumor antigen cross-presentation
                      by type 1 conventional dendritic cells (DCs) in
                      tumor-draining lymph nodes, and subsequently impaired
                      immunotherapy-induced expansion of circulating tumor
                      antigen-specific CD8+ T cells and their accumulation and
                      activation in the TME. In vitro, co-culture of tumor cells
                      undergoing necroptotic but not apoptotic programmed cell
                      death resulted in increased uptake by phagocytic cells,
                      associated with maturation and activation of DCs. Treatment
                      of tumors with the epigenetic modulator azacytidine enhanced
                      intrinsic transcriptional activity of the necroptosis
                      machinery, and hence their susceptibility to ICI
                      immunotherapy. In humans, transcriptome analysis of melanoma
                      samples revealed a strong association between high
                      expression of MLKL and prolonged overall survival and
                      durable clinical response to immunotherapy with anti-PD-1
                      and/or anti-CTLA-4 checkpoint inhibitors.Defective
                      necroptosis signaling in tumor cells is a cancer resistance
                      mechanism to ICI immunotherapy. Reversion of epigenetic
                      silencing of the necroptosis pathway can render tumors
                      susceptible to checkpoint inhibition.},
      keywords     = {Necroptosis: drug effects / Animals / Immune Checkpoint
                      Inhibitors: pharmacology / Immune Checkpoint Inhibitors:
                      therapeutic use / Humans / Mice / Immunotherapy: methods /
                      Drug Resistance, Neoplasm / Neoplasms: drug therapy /
                      Neoplasms: immunology / Tumor Microenvironment / Cell Line,
                      Tumor / Immune Checkpoint Inhibitor (Other) / Immunotherapy
                      (Other) / T cell (Other) / Tumor microenvironment - TME
                      (Other) / Immune Checkpoint Inhibitors (NLM Chemicals)},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40345706},
      doi          = {10.1136/jitc-2024-010433},
      url          = {https://inrepo02.dkfz.de/record/301262},
}