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在肿瘤发展中还有其他作用。VEGF受体如VEGFR2可在多种癌细胞中表达，其激活可促进肿瘤细胞增殖。VEGF还作用于肿瘤微环境中的细胞，如成纤维细胞、骨髓细胞和T细胞，主要支持肿瘤促炎和抑制抗肿瘤免疫反应。在初步实验中，我们发现VEGFR2在效应T细胞（Th1和Th17）和自然调节T细胞中上调。使用CD4+ T细胞中VEGFR2的条件敲除小鼠，我们可以证明CD4+ T细胞中的VEGFR2信号在散发性结直肠癌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。本项目将进一步分析VEGFR2在结直肠癌发展过程中对CD4+ T细胞的功能作用。为了确定肿瘤微环境中表达CD4+ T细胞亚群的VEGFR2功能相关，我们将在小鼠CRC模型中使用各种体内成像策略分析仅限于CD4+ T细胞的VEGFR2报告基因构建。为了进行功能分析，我们将CD4+ T细胞、FoxP3+ Tregs或RORgt+ Th17细胞中VEGFR2的条件敲除小鼠连同或不连同其共受体neuropilin 1暴露于散发性和结肠炎相关癌症的小鼠模型中。然后，我们将在体外和体内分析相关CD4+ T细胞群中VEGFR2信号的生物学功能和潜在的分子机制。总之，本项目获得的数据将增加我们对肿瘤来源的VEGF对肿瘤微环境的影响，其在肿瘤进展中的作用以及CRC抗VEGF治疗的可能后果的认识。

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.