'γδT Cell-IL-17A-Neutrophil' Axis Drives Immunosuppression and Confers Breast Cancer Resistance to High-Dose Anti-VEGFR2 Therapy
نویسندگان
چکیده
Background: Angiogenesis is an essential physiological process and hallmark of cancer. Currently, antiangiogenic therapy, mostly targeting the VEGF/VEGFR2 signaling axis, commonly used in clinic for solid tumors. However, therapies breast cancer patients have produced limited survival benefits since cells rapidly acquire resistance to anti-VEGFR2 therapy. Methods: We tested low-dose high-dose VEGFR2 mAb or VEGFR2-tyrosine kinase inhibitor (TKI) agents 4T1-, EMT6-tumor bearing MMTV-PyMT mouse models. Flow cytometric, western blot tissue immunofluorescence stain were elucidate role regulatory mechanism immune under therapy. Findings: Low-dose VEGFR2-TKI achieved good effects controlling progression multiple models, while high dose treatment was not effective. To further investigate involved regulating this resistance, we found that elicited IL-17A expression γδ T via VEGFR1-PI3K-AKT pathway activation then promoted N2-like neutrophil polarization, thus inducing CD8+ cell exhaustion shape immunosuppressive microenvironment. Combining therapy with IL-17, PD-1 Ly-6G immunomodulatory axis “γδT17 cells-N2 neutrophils” vivo showed promising therapeutic treatment. Interpretation: Taken together, study illustrates potential provides combinational options therapy. Funding Information: This work supported by grants from National Natural Science Foundation China (81930079,81872317,81902981,81902626). Declaration Interests: No conflicts interest disclosed. Ethics Approval Statement: All protocols procedures reviewed approved Ethics Review Committee Second Affiliated Hospital Zhejiang University School Medicine.
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ژورنال
عنوان ژورنال: Social Science Research Network
سال: 2021
ISSN: ['1556-5068']
DOI: https://doi.org/10.2139/ssrn.3829636