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@ARTICLE{Langenbach:277908,
      author       = {M. Langenbach and S. Giesler and S. Richtsfeld and S.
                      Costa-Pereira and L. Rindlisbacher and T. Wertheimer and L.
                      M. Braun and G. Andrieux and S. Duquesne and D. Pfeifer and
                      N. M. Woessner and H. D. Menssen and S. Taromi and J.
                      Duyster and M. Börries and T. Brummer$^*$ and B. R. Blazar
                      and S. Minguet and P. Turko and M. P. Levesque and B. Becher
                      and R. Zeiser},
      title        = {{MDM}2 {I}nhibition {E}nhances {I}mmune {C}heckpoint
                      {I}nhibitor {E}fficacy by {I}ncreasing {IL}15 and {MHC}
                      {C}lass {II} {P}roduction.},
      journal      = {Molecular cancer research},
      volume       = {21},
      number       = {8},
      issn         = {1541-7786},
      address      = {Philadelphia, Pa.},
      publisher    = {AACR},
      reportid     = {DKFZ-2023-01568},
      pages        = {849 - 864},
      year         = {2023},
      abstract     = {The treatment of patients with metastatic melanoma with
                      immune checkpoint inhibitors (ICI) leads to impressive
                      response rates but primary and secondary resistance to ICI
                      reduces progression-free survival. Novel strategies that
                      interfere with resistance mechanisms are key to further
                      improve patient outcome during ICI therapy. P53 is often
                      inactivated by mouse-double-minute-2 (MDM2), which may
                      decrease immunogenicity of melanoma cells. We analyzed
                      primary patient-derived melanoma cell lines, performed bulk
                      sequencing analysis of patient-derived melanoma samples, and
                      used melanoma mouse models to investigate the role of
                      MDM2-inhibition for enhanced ICI therapy. We found increased
                      expression of IL15 and MHC-II in murine melanoma cells upon
                      p53 induction by MDM2-inhibition. MDM2-inhibitor induced
                      MHC-II and IL15-production, which was p53 dependent as Tp53
                      knockdown blocked the effect. Lack of IL15-receptor in
                      hematopoietic cells or IL15 neutralization reduced the
                      MDM2-inhibition/p53-induction-mediated antitumor immunity.
                      P53 induction by MDM2-inhibition caused anti-melanoma immune
                      memory as T cells isolated from MDM2-inhibitor-treated
                      melanoma-bearing mice exhibited anti-melanoma activity in
                      secondary melanoma-bearing mice. In patient-derived melanoma
                      cells p53 induction by MDM2-inhibition increased IL15 and
                      MHC-II. IL15 and CIITA expressions were associated with a
                      more favorable prognosis in patients bearing WT but not
                      TP53-mutated melanoma.MDM2-inhibition represents a novel
                      strategy to enhance IL15 and MHC-II-production, which
                      disrupts the immunosuppressive tumor microenvironment. On
                      the basis of our findings, a clinical trial combining
                      MDM2-inhibition with anti-PD-1 immunotherapy for metastatic
                      melanoma is planned.},
      keywords     = {Animals / Mice / Tumor Suppressor Protein p53: genetics /
                      Tumor Suppressor Protein p53: metabolism / Interleukin-15:
                      metabolism / Interleukin-15: therapeutic use / Immune
                      Checkpoint Inhibitors: pharmacology / Immune Checkpoint
                      Inhibitors: therapeutic use / Cell Line, Tumor / Melanoma:
                      drug therapy / Melanoma: genetics / Antineoplastic Agents:
                      pharmacology / Proto-Oncogene Proteins c-mdm2: metabolism /
                      Tumor Microenvironment / Tumor Suppressor Protein p53 (NLM
                      Chemicals) / Interleukin-15 (NLM Chemicals) / Immune
                      Checkpoint Inhibitors (NLM Chemicals) / Antineoplastic
                      Agents (NLM Chemicals) / Proto-Oncogene Proteins c-mdm2 (NLM
                      Chemicals)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37071397},
      doi          = {10.1158/1541-7786.MCR-22-0898},
      url          = {https://inrepo02.dkfz.de/record/277908},
}