Abstract
Angiogenesis is an essential physiological process and hallmark of cancer. Currently, antiangiogenic therapy, mostly targeting the vascular endothelial growth factor (VEGF)/VEGFR2 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 mAb or VEGFR2-tyrosine kinase inhibitor (TKI) agents in multiple breast cancer mouse models and found that low-dose VEGFR2 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.
Highlights
Pathological angiogenesis is a key feature of cancer and is involved in multiple stages of cancer development [1]
We found that the PI3K-AKT pathway was significantly inhibited in gd T cells sorted from tumors of the lowdose VEGFR2-tyrosine kinase inhibitor (TKI) treatment group
The results showed that the antiIL17A Monoclonal Antibody (mAb) could inhibit N2-phenotype induction in neutrophils mediated by high-dose tumor culture supernatant, while the anti-IFN-g mAb could induce the transformation of neutrophils from the N1 phenotype to the N2 phenotype (Figures 4F, G and Supplementary Figure S4D)
Summary
Pathological angiogenesis is a key feature of cancer and is involved in multiple stages of cancer development [1]. Neovascularization can be enacted by a number of different mechanisms and multiple proangiogenic factors in the tumor microenvironment (such as VEGF and ANG-2) [2]. Antiangiogenic therapies, mostly targeting the VEGF/VEGFR2 signaling, are widely. Immunosuppression Microenvironment and Anti-VEGFR2 Therapy applied in the clinic and considered as a major treatment for a wide range of advanced or metastatic tumors, including breast, colon, lung and gynecological cancers [3, 4]. The efficacy of antiangiogenic drugs in the treatment of breast cancer is inconsistent. The clinical guideline recommendations may not be universally applicable.
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