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@ARTICLE{Pane:241139,
      author       = {A. Pane$^*$ and T. Kordaß$^*$ and A. Hotz-Wagenblatt$^*$
                      and E. Dickes$^*$ and A. Kopp-Schneider$^*$ and R. Will$^*$
                      and B. Seliger and W. Osen$^*$ and S. Eichmüller$^*$},
      title        = {{M}icro{RNA}s affecting the susceptibility of melanoma
                      cells to {CD}8+ {T} cell-mediated cytolysis.},
      journal      = {Clinical and translational medicine},
      volume       = {13},
      number       = {2},
      issn         = {2001-1326},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {DKFZ-2023-00252},
      pages        = {e1186},
      year         = {2023},
      note         = {#EA:D210#LA:D210#},
      abstract     = {The regulatory functions of microRNAs (miRNAs) in
                      anti-tumour immunity have been mainly described in immune
                      effector cells. Since little is known about miRNA effects on
                      the susceptibility of target cells during T cell-target cell
                      interaction, this study focused on the identification of
                      miRNAs expressed in tumour cells controlling their
                      susceptibility to CD8+ T cell-mediated
                      cytotoxicity.Luciferase expressing B16F10 melanoma (B16F10
                      Luci+ ) cells transfected with individual miRNAs covering a
                      comprehensive murine miRNA library were screened for their
                      susceptibility to lysis by an established cytotoxic T
                      lymphocyte (CTL) line (5a, clone Nβ) specific for the
                      melanoma-associated antigen tyrosinase-related protein 2.
                      miRNAs with the most pronounced effects on T cell-mediated
                      lysis were validated and stably expressed in B16F10 cells.
                      In silico analyses identified common targets of miRNA sets
                      determined by the screen, which were further confirmed by
                      small interfering RNA (siRNA)-mediated silencing experiments
                      modulating immune surveillance. The Ingenuity Pathway
                      Analysis (IPA) software and RNA sequencing (RNA-seq) data
                      from miRNA-overexpressing cell lines were applied to
                      investigate the underlying mechanisms. The Cancer Genome
                      Atlas (TCGA)-derived miRNA sequencing data were used to
                      assess the correlation of miRNA expression with melanoma
                      patients' survival.The miRNA screen resulted in the
                      selection of seven miRNAs enhancing CTL-mediated melanoma
                      cell killing in vitro. Upon stable overexpression of
                      selected miRNAs, hsa-miR-320a-3p, mmu-miR-7037-5p and
                      mmu-miR-666-3p were determined as most effective in
                      enhancing susceptibility to CTL lysis. In silico analyses
                      and subsequent siRNA-mediated silencing experiments
                      identified Psmc3 and Ndufa1 as common miRNA targets possibly
                      involved in the functional effects observed. The analyses of
                      RNA-seq data with IPA showed pathways, networks, biological
                      functions and key molecules potentially involved in the
                      miRNA-mediated functional effects. Finally, based on TCGA
                      data analysis, a positive correlation of the conserved
                      miRNAs among the panel of the seven identified miRNAs with
                      overall survival of melanoma patients was determined.For the
                      first time, this study uncovered miRNA species that affect
                      the susceptibility of melanoma cells to T cell-mediated
                      killing. These miRNAs might represent attractive candidates
                      for novel therapy approaches against melanoma and other
                      tumour entities.},
      keywords     = {Humans / Animals / Mice / MicroRNAs: genetics / MicroRNAs:
                      metabolism / Melanoma: genetics / RNA, Small Interfering /
                      CD8-Positive T-Lymphocytes: metabolism / Ndufa1 (Other) /
                      Psmc3 (Other) / cytotoxic T lymphocyte (CTL) (Other) /
                      melanoma (Other) / miRNA (Other) / screening (Other) /
                      MicroRNAs (NLM Chemicals) / RNA, Small Interfering (NLM
                      Chemicals)},
      cin          = {D210 / W610 / C060 / W111},
      ddc          = {610},
      cid          = {I:(DE-He78)D210-20160331 / I:(DE-He78)W610-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)W111-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36718025},
      doi          = {10.1002/ctm2.1186},
      url          = {https://inrepo02.dkfz.de/record/241139},
}