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. Recent studies have 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. Here we investigated the function of VEGFR2+ myeloid cells in regulating tumor immunity and found VEGF induces an immunosuppressive phenotype in VEGFR2+ myeloid cells including directly upregulating the expression of programmed cell death 1-ligand 1 (PD-L1). Moreover, we found that VEGF blockade inhibits the immunosuppressive phenotype of VEGFR2+ myeloid cells, increases T cell activation and enhances the efficacy of immune checkpoint blockade. This study highlights the function of VEGFR2 on myeloid cells and provides mechanistic insight on how VEGF inhibition potentiates immune checkpoint blockade.
Yuqing Zhang, Huocong Huang, Morgan Coleman, Arturas Ziemys, Purva Gopal, Syed M. Kazmi, Rolf A. Brekken