"γδT Cell-IL17A-Neutrophil" Axis Drives Immunosuppression and Confers Breast Cancer Resistance to High-Dose Anti-VEGFR2 Therapy

Angiogenesis is an essential physiological process and hallmark of Cancer. Currently, antiangiogenic therapy, mostly targeting the vascular endothelial growth factor (VEGF)/VEGFR2/KDR/Flk-1 signaling axis, is commonly used in the clinic for solid tumors. However, antiangiogenic therapies for breast Cancer patients have produced limited survival benefits since Cancer cells rapidly resistant to anti-VEGFR2 therapy. We applied the low-dose and high-dose VEGFR2/KDR/Flk-1 mAb or VEGFR2-tyrosine kinase inhibitor (TKI) agents in multiple breast Cancer mouse models and found that low-dose VEGFR2/KDR/Flk-1 mAb or VEGFR2-TKI achieved good effects in controlling Cancer progression, while high-dose treatment was not effective. To further investigate the mechanism involved in regulating the drug resistance, we found that high-dose anti-VEGFR2 treatment elicited IL17A expression in γδ T cells via VEGFR1-PI3K-AKT pathway activation and then promoted N2-like neutrophil polarization, thus inducing CD8⁺ T cell exhaustion to shape an immunosuppressive microenvironment. Combining anti-VEGFR2 therapy with immunotherapy such as IL17A, PD-1 or Ly-6G mAb therapy, which targeting the immunomodulatory axis of "γδT17 cells-N2 neutrophils" in vivo, showed promising therapeutic effects in breast Cancer treatment. This study illustrates the potential mechanism of antiangiogenic therapy resistance in breast Cancer and provides synergy treatment for Cancer.