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The T-box transcription factor Eomesodermin controls CD8+ T cell activity and lymph node metastasis in human colorectal cancer
  1. Imke Atreya
  1. I. Department of Medicine, University of Mainz, Germany
    1. Carl C Schimanski
    1. I. Department of Medicine, University of Mainz, Germany
      1. Christoph Becker
      1. I. Department of Medicine, University of Mainz, Germany
        1. Stefan Wirtz
        1. I. Department of Medicine, University of Mainz, Germany
          1. Heike Dornhoff
          1. I. Department of Medicine, University of Mainz, Germany
            1. Elke Schnuerer
            1. III. Department of Medicine, University of Mainz, Germany
              1. Martin R Berger
              1. DKFZ, University of Heidelberg, Germany
                1. Wolfgang Herr
                1. III. Department of Medicine, University of Mainz, Germany
                  1. Peter R Galle
                  1. I. Department of Medicine, University of Mainz, Germany
                    1. Markus F Neurath (neurath{at}1-med.klinik.uni-mainz.de)
                    1. I. Department of Medicine, University of Mainz, Germany

                      Abstract

                      Background & aims: An efficient cytolytic T cell function is essential for immune-mediated rejection of colorectal cancer. However, the molecular mechanisms driving T cell-mediated cancer rejection are still poorly understood. Here, we assessed the relevance of the T-box transcription factor Eomesodermin in colorectal cancer.

                      Methods & results: By analysing tissue probes from 88 different colorectal tumours, a significant (p<0.02) inverse correlation between Eomesodermin expression in colorectal cancers and the presence of lymph node metastases could be shown, whereas no such correlation was noted for the master transcription factor of regulatory T cells, FoxP3 and CD8alpha expression. To evaluate whether this effect might be due to effects of Eomesodermin on tumor infiltrating CD8+ T cells, we subsequently analyzed the regulated expression and function of this transcription factor in human T cells. Whereas overexpression of this factor induced perforin but not granzyme expression, siRNA mediated suppression of Eomesodermin expression led to significantly reduced IFN-gamma production, perforin levels and cytolytic activity of CD8+ T cells. Furthermore, TGFβ and IL-4 could be identified as important inducer of Eomesodermin expression.

                      Conclusion: These data define for the first time a regulatory role of Eomesodermin for CD8+ T cell activity in humans. Our findings are consistent with a model in which Eomesodermin expression in tumor infiltrating T cells regulates cytolytic functions of CD8+ T cells via perforin expression. These data provide novel insights in control mechanisms governing the functional activity of human CD8+ T lymphocytes via T-box transcription factors in cancer.

                      • colorectal cancer
                      • cytokines
                      • eomesodermin

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