The functional role of VEGFR2-signaling in CD4+ T cells in the pathogenesis of colorectal cancer

血管内皮生长因子被认为是包括结直肠癌（CRC）在内的人类癌症中最重要的血管生成介质之一。然而，最近的数据表明，除了血管生成，VEGF在肿瘤发展中的其他作用。VEGF受体如VEGFR2由各种癌细胞表达，并且它们的活化促进肿瘤细胞增殖。VEGF还作用于肿瘤微环境中的细胞，如成纤维细胞、髓样细胞和T细胞，主要支持肿瘤促炎和抑制抗肿瘤免疫应答。在初步实验中，我们发现效应T细胞（Th1和Th17）和天然调节T细胞中VEGFR2的上调。使用CD4+ T细胞中VEGFR2的条件性敲除小鼠，我们可以证明CD4+ T细胞中的VEGFR2信号传导在散发性CRC小鼠模型中具有保护作用。这些数据清楚地表明，VEGF信号在癌症的适应性免疫中起着以前未被认识到的作用。该项目将进一步分析VEGFR2在CRC发展过程中在CD4+ T细胞中的功能作用。为了鉴定肿瘤微环境中功能相关的表达VEGFR2的CD4+ T细胞亚群，我们将在小鼠CRC模型中用各种体内成像策略分析限制于CD4+ T细胞的VEGFR2报告基因构建体。对于功能分析，我们将暴露条件性敲除小鼠VEGFR2连同或不连同其在CD4+ T细胞、FoxP3+ T细胞或RORgt+ Th17细胞中的共受体神经纤毛蛋白1至散发性和结肠炎相关癌症的小鼠模型。然后，我们将在体外和体内分析相关的CD4+ T细胞群中VEGFR2信号传导的生物学功能和潜在的分子机制。总之，本项目中获得的数据将增加我们对肿瘤源性VEGF对肿瘤微环境的影响，其对肿瘤进展的作用以及CRC中抗VEGF治疗的可能后果的了解。

Vascular endothelial growth factor is regarded as one of the most important mediators of angiogenesis in human cancers including colorectal cancer (CRC). However, recent data suggest additional roles for VEGF besides angiogenesis in tumor development. VEGF receptors such as VEGFR2 are expressed by various cancer cells and their activation promotes tumor cell proliferation. VEGF also acts on cells in the tumor microenvironment such as fibroblasts, myeloid cells and T cells, mainly to support tumor promoting-inflammation and inhibit the anti-tumor immune response. In preliminary experiments, we found an upregulation of VEGFR2 in effector T cells (Th1 and Th17) and natural regulator T cells. Using conditional knockout mice for VEGFR2 in CD4+ T cells, we could show that VEGFR2 signaling in CD4+ T cells has protective effects in a mouse model of sporadic CRC. These data clearly show that VEGF signaling plays a previously unrecognized role in adaptive immunity in cancer. This project will further analyze the functional role of VEGFR2 in CD4+ T cells during CRC development. In order to identify the functionally relevant VEGFR2 expressing CD4+ T cell subpopulation in the tumor microenvironment, we will analyze VEGFR2 reporter constructs restricted to CD4+ T cells with various in vivo imaging strategies in mouse CRC models. For functional analysis, we will expose conditional knockout mice for VEGFR2 together with or without its co-receptor neuropilin 1 in CD4+ T cells, FoxP3+ Tregs or RORgt+ Th17 cells to mouse models of sporadic and colitis-associated cancer. We will then analyze the biologial function and underlying molecular mechanisms of VEGFR2 signaling in relevant CD4+ T cell populations in vitro and in vivo. Together, the data acquired in this project will increase our knowledge about the effects of tumor derived VEGF on the tumor microenvironment, its role for tumor progression and possible consequences for anti-VEGF therapy in CRC.