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

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

  • Front Immunol. 2021 Oct 15;12:699478. doi: 10.3389/fimmu.2021.699478.
Zhigang Zhang 1 2,  Chenghui Yang 3,  Lili Li 2 4,  Ying Zhu 1,  Ke Su 2,  Lingyun Zhai 1,  Zhen Wang 2 5,  Jian Huang 2 5 6
Affiliations

Affiliations

  • 1 Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Department of Breast Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
  • 4 Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Cancer Center, Zhejiang University, Hangzhou, China.
PMID: 34721375 DOI: 10.3389/fimmu.2021.699478
Abstract

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.

Keywords

IL17A; anti-VEGFR2 therapy; breast cancer; neutrophil; therapy resistance; γδT cell.

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