Anti-angiogenesis therapy overcomes the innate resistance to PD-1/PD-L1 blockade in VEGFA-overexpressed mouse tumor models

The effectual clinical benefits of immune checkpoint inhibitor (ICI) are hampered by a high rate of innate resistance, and VEGFA may contribute to ICI treatment resistance. In this study, we endeavored to assess the tumor microenvironment (TME) in VEGFA-overexpressed human tumors and mouse tumor models, and to explore whether anti-angiogenesis therapy can overcome the innate resistance to ICI in hyperangiogenesis mouse tumor models and the underlying mechanism. Effect of VEGFA on clinical prognosis and TME was analyzed using TCGA data. The VEGFA-overexpressed mouse breast and colon subcutaneous models were established. PD-1 mAb or apatinib alone and combination therapy were used. Immunohistochemistry and immunofluorescence were used to assess angiogenesis and hypoxia. Flow cytometry, RNA sequencing and MCP-counter were applied to detect tumor immunomicroenvironment. High level of VEGFA mRNA in human tumors is related to poor prognosis and hypoxic, angiogenic and immunosuppressive TME. Upregulation of VEGFA increased the degree of malignancy of tumor cells in vitro and in vivo. VEGFA-overexpressed models were characterized by hypoxic, hyperangiogenic and immunosuppressive TME and indicated innate resistance to ICI. In tumor-bearing mice without VEGFA overexpression, the combination therapy had no synergistic anti-tumor effect compared to monotherapy. However, apatinib alleviated hyperangiogenesis and hypoxia in TME and converted the immunosuppressive TME into an immunostimulatory one in VEGFA-overexpressed tumors. Thus, anti-angiogenesis therapy could improve the efficiency of ICI in VEGFA-overexpressed tumors. Revealing whether there is hypervascularization in tumor tissues may help to clarify the adoption of anti-angiogenesis and ICI combination therapy or ICI monotherapy in cancer treatment.