The Immunosuppressive Function of VEGF Signaling in the Tumor Microenvironment

dc.contributor.advisorAguilera, Todd A.en
dc.contributor.committeeMemberBrekken, Rolf A.en
dc.contributor.committeeMemberCastrillon, Diego H.en
dc.contributor.committeeMemberDellinger, Michael T.en
dc.creatorZhang, Yuqingen
dc.creator.orcid0000-0003-0740-5310 2021 2021
dc.description.abstractAngiogenesis, a hallmark of cancer, is induced by vascular endothelial growth factor-A (VEGF). As a result, anti-VEGF therapy is commonly employed for cancer treatment. However, anti-VEGF therapy generally provides modest efficacy in cancer patients and therapy-induced hypoxia results in a less differentiated mesenchymal-like tumor cell phenotype, which reinforces the need for effective companion therapies. Cyclooxygenase-2 (COX-2) inhibition has been shown to promote tumor cell differentiation and improve standard therapy response in pancreatic cancer. Here, I evaluate the efficacy of COX-2 inhibition and VEGF blockade in preclinical models of pancreatic cancer and identity it as a strategy to overcome therapy-induced resistance in pancreatic cancer. Combination therapy reverses anti-VEGF-induced epithelial-mesenchymal transition, collagen deposition and promotes an immune stimulatory microenvironment. Recent studies have also found that VEGF expression is also associated with immune suppression in cancer patients. This connection has been investigated in preclinical and clinical studies by evaluating the therapeutic effect of combining anti-angiogenic reagents with immune therapy. However, the mechanisms of how anti-VEGF strategies enhance immune therapy are not fully understood. We and others have shown selective elevation of VEGFR2 expression on tumor-associated myeloid cells in tumor-bearing animals. I further investigate the function of VEGFR2+ myeloid cells in regulating tumor immunity and find VEGF induces an immunosuppressive phenotype in VEGFR2+ myeloid cells including directly upregulating the expression of programmed cell death 1-ligand 1 (PD-L1). Moreover, I demonstrate that VEGF blockade inhibits the immunosuppressive phenotype of VEGFR2+ myeloid cells, increases T cell activation and enhances the efficacy of immune checkpoint blockade. These studies highlight the function of VEGFR2 on myeloid cells and provide mechanistic insight on how VEGF inhibition potentiates immune checkpoint blockade.en
dc.subjectAngiogenesis Inhibitorsen
dc.subjectCyclooxygenase 2en
dc.subjectMyeloid Cellsen
dc.subjectPancreatic Neoplasmsen
dc.subjectTumor Microenvironmenten
dc.subjectVascular Endothelial Growth Factor Aen
dc.titleThe Immunosuppressive Function of VEGF Signaling in the Tumor Microenvironmenten
dc.type.materialtexten School of Biomedical Sciencesen Biologyen Southwestern Medical Centeren of Philosophyen


Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
43.07 MB
Adobe Portable Document Format

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
1.84 KB
Plain Text