Calcineurin-dependent effects of T cells in intestinal tumor development

结直肠癌(CRC)是肠上皮细胞(IECS)体细胞突变积累的结果。虽然在炎症性肠病(IBD)中观察到的慢性肠道炎症是CRC发生的危险因素，但在没有临床明显炎症的情况下，与炎症相关的途径也有助于结直肠癌的发生。钙调神经磷酸酶是一种在免疫中起核心作用的丝氨酸/苏氨酸磷酸酶，最近我们证明它不仅在专业免疫细胞中活跃，而且在IECS中也活跃，它通过依赖于活化T细胞核因子家族(NFAT)的转录因子促进结直肠癌的发生。这些数据证明了钙调神经磷酸酶和NFAT在肠道肿瘤细胞中的致癌作用，但与之前观察到的钙调神经磷酸酶抑制剂系统治疗增加人类和小鼠肠道肿瘤发展形成对比。因此，我们研究了钙调神经磷酸酶是否以细胞特异性的方式调节CRC，特别是钙调神经磷酸酶是否在T细胞内发挥肿瘤抑制和保护作用，后者的全身抑制促进了肿瘤的发展。根据这一概念，小鼠体内T细胞特异性钙调神经磷酸酶的缺失促进了肠道肿瘤的发展。在这里，我们建议研究钙调神经磷酸酶在T细胞中保护和抑制肿瘤作用的分子基础。具体地说，我们建议(I)研究钙调神经磷酸酶的保护功能是否由CD4+或CD8+T细胞介导，以及这种作用是依赖于钙调神经磷酸酶在T细胞中的内在作用，还是通过间接调节其他肿瘤浸润性免疫细胞来实现。此外，我们将(Ii)研究钙调神经磷酸酶的保护作用是否由NFAT或其他因素介导，以及它们是否源于钙调神经磷酸酶对T细胞代谢的依赖调节。最后，(Iii)我们建议确定钙调神经磷酸酶参与调节肠道肿瘤发展的分子靶点，并研究它们作为结直肠癌预后标志物和治疗靶点的价值。总之，这一建议将为肠道肿瘤发展的发病机制提供新的见解，并确定潜在的预后标志物和治疗靶点。

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.