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@ARTICLE{Marquardt:186754,
      author       = {V. Marquardt$^*$ and J. Theruvath and D. Pauck$^*$ and D.
                      J. Picard$^*$ and N. Qin$^*$ and L. Blümel$^*$ and M.
                      Maue$^*$ and J. Bartl$^*$ and U. Ahmadov$^*$ and M.
                      Langini$^*$ and F.-D. Meyer$^*$ and A. Cole and J. Cruz-Cruz
                      and C. M. Graef and M. Wölfl and T. Milde and O. Witt$^*$
                      and A. Erdreich-Epstein and G. Leprivier$^*$ and U. Kahlert
                      and A. Stefanski and K. Stühler and S. T. Keir and D. D.
                      Bigner and J. Hauer and T. Beez and C. B. Knobbe-Thomsen$^*$
                      and U. Fischer and J. Felsberg$^*$ and F. K. Hansen and R.
                      Vibhakar and S. Venkatraman and S. H. Cheshier and G.
                      Reifenberger$^*$ and A. Borkhardt$^*$ and T. Kurz and M.
                      Remke$^*$ and S. Mitra},
      title        = {{T}acedinaline ({CI}-994), a class {I} {HDAC} inhibitor,
                      targets intrinsic tumor growth and leptomeningeal
                      dissemination in {MYC}-driven medulloblastoma while making
                      them susceptible to anti-{CD}47-induced macrophage
                      phagocytosis via {NF}-k{B}-{TGM}2 driven tumor
                      inflammation.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {11},
      number       = {1},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2023-00098},
      pages        = {e005871},
      year         = {2023},
      abstract     = {While major advances have been made in improving the
                      quality of life and survival of children with most forms of
                      medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB)
                      still suffer significant morbidity and mortality. There is
                      an urgent need to explore multimodal therapeutic regimens
                      which are effective and safe for children. Large-scale
                      studies have revealed abnormal cancer epigenomes caused by
                      mutations and structural alterations of chromatin modifiers,
                      aberrant DNA methylation, and histone modification
                      signatures. Therefore, targeting epigenetic modifiers for
                      cancer treatment has gained increasing interest, and
                      inhibitors for various epigenetic modulators have been
                      intensively studied in clinical trials. Here, we report a
                      cross-entity, epigenetic drug screen to evaluate therapeutic
                      vulnerabilities in MYC amplified MB, which sensitizes them
                      to macrophage-mediated phagocytosis by targeting the
                      CD47-signal regulatory protein α (SIRPα) innate checkpoint
                      pathway.We performed a primary screen including 78
                      epigenetic inhibitors and a secondary screen including 20
                      histone deacetylase inhibitors (HDACi) to compare response
                      profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11),
                      MB (n=14), and glioblastoma (n=14). This unbiased approach
                      revealed the preferential activity of HDACi in MYC-driven
                      MB. Importantly, the class I selective HDACi, CI-994, showed
                      significant cell viability reduction mediated by induction
                      of apoptosis in MYC-driven MB, with little-to-no activity in
                      non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We
                      tested the combinatorial effect of targeting class I HDACs
                      and the CD47-SIRPa phagocytosis checkpoint pathway using in
                      vitro phagocytosis assays and in vivo orthotopic xenograft
                      models.CI-994 displayed antitumoral effects at the primary
                      site and the metastatic compartment in two orthotopic mouse
                      models of MYC-driven MB. Furthermore, RNA sequencing
                      revealed nuclear factor-kB (NF-κB) pathway induction as a
                      response to CI-994 treatment, followed by transglutaminase 2
                      (TGM2) expression, which enhanced inflammatory cytokine
                      secretion. We further show interferon-γ release and cell
                      surface expression of engulfment ('eat-me') signals (such as
                      calreticulin). Finally, combining CI-994 treatment with an
                      anti-CD47 mAb targeting the CD47-SIRPα phagocytosis
                      checkpoint enhanced in vitro phagocytosis and survival in
                      tumor-bearing mice.Together, these findings suggest a
                      dynamic relationship between MYC amplification and innate
                      immune suppression in MYC amplified MB and support further
                      investigation of phagocytosis modulation as a strategy to
                      enhance cancer immunotherapy responses.},
      keywords     = {Brain Neoplasms (Other) / Cytotoxicity, Immunologic (Other)
                      / Immunotherapy (Other) / Macrophages (Other) / Phagocytosis
                      (Other)},
      cin          = {ED01 / B310 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331 / I:(DE-He78)B310-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36639156},
      doi          = {10.1136/jitc-2022-005871},
      url          = {https://inrepo02.dkfz.de/record/186754},
}