VEGFR2 activity on myeloid cells mediates immune suppression in the tumor microenvironment

Abstract

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 tumorbearing 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.

Direct and indirect regulation of the tumor immune microenvironment by VEGF

“…VEGFR2 leads to the down-regulation of PD-L1 on myeloid cells. 130 Considering that PD-L1 expression on host bone marrow-derived cells is essential for the response to PD-L1 blockade, 189 our data suggest that anti-VEGF therapy might benefit from combination with immune checkpoint molecules other than PD-1/PD-L1. Indeed, we found that the efficacy of combining VEGF-specific blockade with anti-CTLA-4 antibodies is superior to combination with PD-1 blockade in a breast cancer syngeneic model.…”

“…Vegfr2-deleted mouse model 130 colon cancer model. 106,130,131 Sunitinib inhibited MDSC recruitment via VEGFR inhibition and/or the inhibition of STAT3 in MDSCs.…”

“…Vegfr2-deleted mouse model 130 colon cancer model. 106,130,131 Sunitinib inhibited MDSC recruitment via VEGFR inhibition and/or the inhibition of STAT3 in MDSCs. 132 Sunitinib treatment or selective inhibition of VEGF binding to VEGFR2 also significantly decreased PD-L1 expression on MDSCs and other myeloid cells.…”

“…Therefore, it is reasonable to restrain MDSC accumulation and reverse the immunosuppressive function by disrupting the VEGF‐VEGFR2 axis. We and others have demonstrated that multiple anti‐VEGF strategies, including the use of antibodies and sunitinib, can decrease the number of MDSCs and result in less T cell suppressive capacity in inflammatory 4T1 breast cancer model and MC38 colon cancer model 106,130,131 . Sunitinib inhibited MDSC recruitment via VEGFR inhibition and/or the inhibition of STAT3 in MDSCs 132 .…”

“…Sunitinib inhibited MDSC recruitment via VEGFR inhibition and/or the inhibition of STAT3 in MDSCs 132 . Sunitinib treatment or selective inhibition of VEGF binding to VEGFR2 also significantly decreased PD‐L1 expression on MDSCs and other myeloid cells 130,131 . The depletion of MDSCs caused by sunitinib treatment further benefits vaccine efficacy and leads to an enhanced antigen‐specific T‐cell response in preclinical tumor models 133 .…”