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@ARTICLE{Hrvat:282729,
      author       = {A. Hrvat and M. Schmidt and B. Wagner and D. Zwanziger and
                      R. Kimmig and L. Volbracht and S. Brandau$^*$ and N.
                      Mallmann-Gottschalk},
      title        = {{E}lectrolyte imbalance causes suppression of {NK} and {T}
                      cell effector function in malignant ascites.},
      journal      = {Journal of experimental $\&$ clinical cancer research},
      volume       = {42},
      number       = {1},
      issn         = {0392-9078},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2023-01855},
      pages        = {235},
      year         = {2023},
      abstract     = {Malignant ascites commonly occurs in advanced or recurrent
                      stages of epithelial ovarian cancer during peritoneal
                      carcinomatosis and is correlated with poor prognosis. Due to
                      its complex composition of cellular and acellular components
                      malignant ascites creates a unique tumor microenvironment,
                      which mediates immunosuppression and promotes progression of
                      disease. However, the immunosuppressive mechanisms remain
                      poorly understood.In the present study, we explored the
                      antitumor activity of healthy donor NK and T cells directed
                      against ovarian cancer cells in presence of malignant
                      ascites derived from patients with advanced or recurrent
                      peritoneal carcinomatosis. A wide range of methods was used
                      to study the effect of ascites on NK and T cells (FACS,
                      ELISA, EliSpot, qPCR, Live-cell and confocal microscopy,
                      Western blot and electrolyte flux assays). The ascites
                      components were assessed using quantitative analysis
                      (nephelometry, potentiometry and clinical chemistry) and
                      separation methods (dialysis, ultracentrifugal filtration
                      and lipid depletion).Ascites rapidly inhibited NK cell
                      degranulation, tumor lysis, cytokine secretion and calcium
                      signaling. Similarly, target independent NK and T cell
                      activation was impaired in ascites environment. We
                      identified imbalanced electrolytes in ascites as crucial
                      factors causing extensive immunosuppression of NK and T
                      cells. Specifically, high sodium, low chloride and low
                      potassium content significantly suppressed NK-mediated
                      cytotoxicity. Electrolyte imbalance led to changes in
                      transcription and protein expression of electrolyte channels
                      and impaired NK and T cell activation. Selected inhibitors
                      of sodium electrolyte channels restored intracellular
                      calcium flux, conjugation, degranulation and transcript
                      expression of signaling molecules. The levels of
                      ascites-mediated immunosuppression and
                      sodium/chloride/potassium imbalance correlated with poor
                      patient outcome and selected molecular alterations were
                      confirmed in immune cells from ovarian cancer patients.Our
                      data suggest a novel electrolyte-based mechanism of
                      immunosuppression in malignant ascites of patients with
                      peritoneal carcinomatosis. We show for the first time that
                      the immunosuppression of NK cytotoxicity in coculture assays
                      is correlated to patient poor survival. Therapeutic
                      application of sodium channel inhibitors may provide new
                      means for restoring immune cell activity in ascites or
                      similar electrolyte imbalanced environments.},
      keywords     = {Humans / Female / Peritoneal Neoplasms / Ascites /
                      Chlorides / T-Lymphocytes / Ovarian Neoplasms / Potassium /
                      Tumor Microenvironment / Amiloride (Other) / Ascites (Other)
                      / Channel blocker (Other) / Chloride (Other) / Electrolyte
                      (Other) / Immunosuppression (Other) / NK cell (Other) /
                      Ovarian cancer (Other) / Sodium (Other) / T cell (Other) /
                      Chlorides (NLM Chemicals) / Potassium (NLM Chemicals)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37684704},
      pmc          = {pmc:PMC10485936},
      doi          = {10.1186/s13046-023-02798-8},
      url          = {https://inrepo02.dkfz.de/record/282729},
}