VEGF165b and its mutant demonstrate immunomodulatory, not merely anti-angiogenic functions, in tumor-bearing mice

Abstract

A great deal of evidence has shown that anti-angiogenic molecules and antibodies targeting the VEGF-A/VEGFRs signal pathway can also reverse tumor-induced immunosuppression to an extent. VEGF165b, an anti-angiogenic VEGF-A isoform, has demonstrated capacity as an efficacious anti-tumor therapy in mice as an anti-angiogenic agent. However, whether VEGF165b also plays an immunomodulatory role in anti-tumor field remains unclear. mVEGF165b effect on regulatory T cells (Tregs) in vitro were evaluated using flow cytometry and Cell Counting Kit-8 (CCK-8) methods. Its effects on Tregs (or Foxp3 expressing cells) and myeloid-derived suppressor cells (MDSCs) were analyzed in vivo using flow cytometry and immunostaining techniques. In this study, we found VEGF165b and its mutant (its half-life in plasma was extended 10 times while retaining its bioactivity; the VEGF165b mutant is called mVEGF165b for short) inhibited the proliferation of Tregs in vitro. In addition, mVEGF165b dramatically inhibited the accumulation of MDSCs and Tregs (or Foxp3 expressing cells) in the spleen and tumor in tumor-bearing mice. In conclusion, our findings demonstrated for the first time that VEGF165b and its mutant has immunoregulatory functions. It may be used as a potential immunomodulatory agent, beyond its anti-angiogenic capacities, in cancer therapies.

Keywords: Immunosuppressive cells; Immunotherapy; MDSCs; Tregs; VEGF165b.