'γδTcells-IL-17A-Neutrophils' Axis Drive Immunosuppression and Confer VEGFR2-TKI Refractoriness to Breast Cancer Therapy

Abstract

Angiogenesis is an essential physiological process and hallmark for cancer, currently the antiangiogenic therapy is commonly used in clinic for solid tumor. But antiangiogenic therapies for breast cancer provide limited survival benefit, since cancer cells rapidly acquired resistance against antiangiogenic agents. However, the mechanism involved in regulating the resistance has not been further studied. Here, based on breast cancer mouse model, we demonstrated that treatment with high dose of VEGFR2-TKI not effective in controlling breast cancer progression. High dose of VEGFR2-TKI elicits IL-17A expression of γδT cells, resulting from directly acting on VEGFR2. IL-17A subsequently promotes the polarization of neutrophils to the “N2” type, which could induce CD8+ T cells exhaustion and eventually shape an immunosuppressive microenvironment. Overall, our work uncovered an immunomodulatory axis of “VEGFR2-TKI-γδT17 cells-N2 neutrophils” instigate resistant response to VEGFR2-TKI therapy, and provided a novel strategy to improve the efficacy of antiangiogenic therapy for breast cancer. Funding Statement: This work was supported by National Natural Science Foundation of China (No. 81902626, 81902981 and 81872317). Declaration of Interests: The authors declare that there are no potential conflicts of interest. Ethics Approval Statement: All mouse protocols and procedures were reviewed and approved by Ethic Review Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine.