Calcineurin-dependent effects of T cells in intestinal tumor development

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Colorectal cancer (CRC) develops as a consequence of the accumulation of somatic mutations in intestinal epithelial cells (IECs). While chronic intestinal inflammation as observed in inflammatory bowel disease (IBD) is a risk factor for the development of CRC, inflammation-associated pathways also contribute to colorectal carcinogenesis in the absence of clinically overt inflammation. We could recently demonstrate that calcineurin, a serine/threonine-phosphatase with central roles in immunity, is not only active in professional immune cells but also in IECs, where it promotes colorectal carcinogenesis in a manner dependent on transcription factors of the family of nuclear factor of activated T cells (NFAT). These data demonstrate oncogenic roles of calcineurin and NFAT in intestinal tumor cells but contrast with previous observations of increased intestinal tumor development in humans and mice systemically treated with calcineurin inhibitors. We therefore investigated whether calcineurin regulates CRC in a cell-specific manner and specifically whether calcineurin exerts tumor-inhibiting, protective roles within T cells, whose systemic inhibition promotes tumor development. In accordance with this concept, T cell-specific deletion of calcineurin in mice promoted intestinal tumor development. Here, we propose to investigate the molecular basis of protective, tumor-inhibiting roles of calcineurin in T cells. Specifically, we propose to (i) investigate whether protective functions of calcineurin are mediated by CD4+ or CD8+ T cells and whether such effects are dependent on cell-intrinsic roles of calcineurin in T cells or occur through indirect modulation of other tumor-infiltrating immune cells. In addition, we will (ii) investigate whether protective effects of calcineurin are mediated by NFAT or other factors and whether they result from calcineurin-dependent regulation of T cell metabolism. Finally, (iii) we propose to identify the molecular targets of calcineurin involved in the regulation of intestinal tumor development and to study their value as prognostic markers and therapeutic targets in CRC. Together, this proposal will provide novel insight into the pathogenesis of intestinal tumor development and identify potential prognostic markers and therapeutic targets in CRC.