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@ARTICLE{Sorrentino:180022,
      author       = {A. Sorrentino$^*$ and A. N. Menevse and T. Michels$^*$ and
                      V. Volpin$^*$ and F. C. Durst and J. Sax and M. Xydia and A.
                      Hussein and S. Stamova and S. Spoerl and N. Heuschneider and
                      J. Muehlbauer and K. M. Jeltsch and A. Rathinasamy and M.
                      Werner-Klein and M. Breinig$^*$ and D. Mikietyn and C.
                      Kohler and I. Poschke$^*$ and S. Purr$^*$ and O. Reidell and
                      C. Martins Freire and R. Offringa$^*$ and C. Gebhard and R.
                      Spang and M. Rehli and M. Boutros$^*$ and C. Schmidl and N.
                      Khandelwal$^*$ and P. Beckhove$^*$},
      title        = {{S}alt-inducible kinase 3 protects tumor cells from
                      cytotoxic {T}-cell attack by promoting {TNF}-induced
                      {NF}-κ{B} activation.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {10},
      number       = {5},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2022-01039},
      pages        = {e004258},
      year         = {2022},
      note         = {#EA:D015#},
      abstract     = {Cancer immunotherapeutic strategies showed unprecedented
                      results in the clinic. However, many patients do not respond
                      to immuno-oncological treatments due to the occurrence of a
                      plethora of immunological obstacles, including tumor
                      intrinsic mechanisms of resistance to cytotoxic T-cell (TC)
                      attack. Thus, a deeper understanding of these mechanisms is
                      needed to develop successful immunotherapies.To identify
                      novel genes that protect tumor cells from effective
                      TC-mediated cytotoxicity, we performed a genetic screening
                      in pancreatic cancer cells challenged with
                      tumor-infiltrating lymphocytes and antigen-specific TCs.The
                      screening revealed 108 potential genes that protected tumor
                      cells from TC attack. Among them, salt-inducible kinase 3
                      (SIK3) was one of the strongest hits identified in the
                      screening. Both genetic and pharmacological inhibitions of
                      SIK3 in tumor cells dramatically increased TC-mediated
                      cytotoxicity in several in vitro coculture models, using
                      different sources of tumor and TCs. Consistently, adoptive
                      TC transfer of TILs led to tumor growth inhibition of
                      SIK3-depleted cancer cells in vivo. Mechanistic analysis
                      revealed that SIK3 rendered tumor cells susceptible to tumor
                      necrosis factor (TNF) secreted by tumor-activated TCs. SIK3
                      promoted nuclear factor kappa B (NF-κB) nuclear
                      translocation and inhibited caspase-8 and caspase-9 after
                      TNF stimulation. Chromatin accessibility and transcriptome
                      analyses showed that SIK3 knockdown profoundly impaired the
                      expression of prosurvival genes under the TNF-NF-κB axis.
                      TNF stimulation led to SIK3-dependent phosphorylation of the
                      NF-κB upstream regulators inhibitory-κB kinase and
                      NF-kappa-B inhibitor alpha on the one side, and to
                      inhibition of histone deacetylase 4 on the other side, thus
                      sustaining NF-κB activation and nuclear stabilization. A
                      SIK3-dependent gene signature of TNF-mediated NF-κB
                      activation was found in a majority of pancreatic cancers
                      where it correlated with increased cytotoxic TC activity and
                      poor prognosis.Our data reveal an abundant molecular
                      mechanism that protects tumor cells from cytotoxic TC attack
                      and demonstrate that pharmacological inhibition of this
                      pathway is feasible.},
      keywords     = {CD8-positive T-lymphocytes (Other) / cytokines (Other) /
                      immunomodulation (Other) / immunotherapy (Other) / tumor
                      escape (Other)},
      cin          = {D015 / F190 / D200 / D170 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)D015-20160331 / I:(DE-He78)F190-20160331 /
                      I:(DE-He78)D200-20160331 / I:(DE-He78)D170-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35606086},
      doi          = {10.1136/jitc-2021-004258},
      url          = {https://inrepo02.dkfz.de/record/180022},
}