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

• Applicant: Professor Dr. Maximilian Waldner, Ph.D.
• Subject Area: Gastroenterology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280163318

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.

• DFG Programme: Research Units
• Subproject of: FOR 2438: Cell Plasticity in Colorectal Carcinogenesis