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@ARTICLE{Sonner:130583,
      author       = {J. K. Sonner$^*$ and K. Deumelandt$^*$ and M. Ott$^*$ and
                      C. M. Thomé and K. Rauschenbach$^*$ and S. Schulz$^*$ and
                      B. Munteanu and S. R. Mohapatra$^*$ and I. Adam$^*$ and
                      A.-C. Hofer$^*$ and M. Feuerer$^*$ and C. Opitz$^*$ and C.
                      Hopf$^*$ and W. Wick$^*$ and M. Platten$^*$},
      title        = {{T}he stress kinase {GCN}2 does not mediate suppression of
                      antitumor {T} cell responses by tryptophan catabolism in
                      experimental melanomas.},
      journal      = {OncoImmunology},
      volume       = {5},
      number       = {12},
      issn         = {2162-402X},
      address      = {Austin, Tex.},
      publisher    = {Landes Bioscience},
      reportid     = {DKFZ-2017-05662},
      pages        = {e1240858 -},
      year         = {2016},
      abstract     = {Tryptophan metabolism is a key process that shapes the
                      immunosuppressive tumor microenvironment. The two
                      rate-limiting enzymes that mediate tryptophan depletion,
                      indoleamine-2,3-dioxygenase (IDO) and
                      tryptophan-2,3-dioxygenase (TDO), have moved into the focus
                      of research and inhibitors targeting IDO and TDO have
                      entered clinical trials. Local tryptophan depletion is
                      generally viewed as the crucial immunosuppressive mechanism.
                      In T cells, the kinase general control non-derepressible 2
                      (GCN2) has been identified as a molecular sensor of
                      tryptophan deprivation. GCN2 activation by tryptophan
                      depletion induces apoptosis and mitigates T cell
                      proliferation. Here, we investigated whether GCN2 attenuates
                      tumor rejection in experimental B16 melanoma using T
                      cell-specific Gcn2 knockout mice. Our data demonstrate that
                      GCN2 in T cells did not affect immunity to B16 tumors even
                      when animals were treated with antibodies targeting
                      cytotoxic T lymphocyte antigen-4 (CTLA4). GCN2-deficient
                      gp100 TCR-transgenic T cells were equally effective as
                      wild-type pmel T cells against gp100-expressing B16
                      melanomas after adoptive transfer and gp100 peptide
                      vaccination. Even augmentation of tumoral tryptophan
                      metabolism in B16 tumors by lentiviral overexpression of Tdo
                      did not differentially affect GCN2-proficient vs.
                      GCN2-deficient T cells in vivo. Importantly, GCN2 target
                      genes were not upregulated in tumor-infiltrating T cells.
                      MALDI-TOF MS imaging of B16 melanomas demonstrated
                      maintenance of intratumoral tryptophan levels despite high
                      tryptophan turnover, which prohibits a drop in tryptophan
                      sufficient to activate GCN2 in tumor-infiltrating T cells.
                      In conclusion, our results do not suggest that suppression
                      of antitumor immune responses by tryptophan metabolism is
                      driven by local tryptophan depletion and subsequent
                      GCN2-mediated T cell anergy.},
      cin          = {G160 / G370 / D100 / G161 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)G160-20160331 / I:(DE-He78)G370-20160331 /
                      I:(DE-He78)D100-20160331 / I:(DE-He78)G161-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28123877},
      pmc          = {pmc:PMC5214097},
      doi          = {10.1080/2162402X.2016.1240858},
      url          = {https://inrepo02.dkfz.de/record/130583},
}