Calcineurin-dependent effects of T cells in intestinal tumor development

结直肠癌（CRC）的发展是肠上皮细胞（IEC）中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发展的风险因素，但在没有临床明显炎症的情况下，炎症相关途径也有助于结直肠癌的发生。我们最近可以证明，钙调神经磷酸酶，丝氨酸/苏氨酸磷酸酶与免疫的核心作用，不仅是活跃的专业免疫细胞，但也在IEC，在那里它促进结直肠癌的发生依赖于转录因子的活化T细胞（NFAT）家族。这些数据证明了钙调磷酸酶和NFAT在肠肿瘤细胞中的致癌作用，但与先前观察到的用钙调磷酸酶抑制剂全身治疗的人和小鼠中肠肿瘤发展增加形成对比。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，其全身抑制促进肿瘤发展。根据这一概念，T细胞特异性缺失小鼠中的钙调神经磷酸酶促进了肠道肿瘤的发展。 在这里，我们建议调查的保护，肿瘤抑制作用的钙调磷酸酶在T细胞的分子基础。具体而言，我们建议（i）研究钙调神经磷酸酶的保护功能是否由CD 4+或CD 8 + T细胞介导，以及这种作用是否依赖于T细胞中钙调神经磷酸酶的细胞内在作用或通过间接调节其他肿瘤浸润免疫细胞而发生。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，以及它们是否由钙调神经磷酸酶依赖的T细胞代谢调节引起。最后，（iii）我们建议确定钙调神经磷酸酶参与肠道肿瘤发展的调节的分子靶点，并研究其作为结直肠癌预后标志物和治疗靶点的价值。总之，这一提议将为肠道肿瘤发展的发病机制提供新的见解，并确定CRC中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.