Browsing by Subject "Angiogenesis Inhibitors"
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Item The Immunosuppressive Function of VEGF Signaling in the Tumor Microenvironment(December 2021) Zhang, Yuqing; Aguilera, Todd A.; Brekken, Rolf A.; Castrillon, Diego H.; Dellinger, Michael T.Angiogenesis, 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.Item Understanding the Mechanism of Action of UV3, an Anti-CD54 Monoclonal Antibody, in the Therapy of Multiple Myeloma(2005-05-04) Coleman, Elaine J.; Vitetta, Ellen S.Multiple myeloma is a hematopoietic malignancy involving the uncontrolled proliferation of a single clone of plasma cells or plasma cell progenitors in the bone marrow. Previously, a monoclonal antibody called UV3, which recognizes human CD54/ICAM-1, was developed for the therapy of multiple myeloma. UV3 is highly effective at treating advanced multiple myeloma in SCID mice with human multiple myeloma xenografts. UV3 does not inhibit homotypic tumor cell adhesion or their adhesion to the bone marrow. UV3 does not induce apoptosis of tumor cells or block cell growth. Previous work evaluating F(ab)'2 fragments of UV3 demonstrated that they were effective in mediating anti-tumor activity, suggesting that other mechanisms also contributed to the anti-tumor activity of UV3. One possibility to explain how UV3 exerts its anti-tumor activity could be that UV3 inhibits the secretion of pro-angiogenic cytokines and molecules, resulting in an inhibition of angiogenesis. To this end, our goal was to evaluate the angiogenic signals from human multiple myeloma cells and determine whether UV3 would interfere with such signals. In addition, we further examined the role of the Fc portion of UV3 in mediating anti-tumor activity. We found that multiple myeloma cell lines secrete some pro-angiogenic cytokines and molecules, and although UV3 may induce a minor anti-angiogenic effect, the Fc portion of UV3 was critical for its anti-tumor activity. In addition, we found that UV3 prolonged the survival of SCID mice with Daudi lymphoma, which suggests UV3 may be effective in treating a variety of hematological malignancies.