Tumor-associated neutrophils activated by tumor-derived CCL20 (C-C motif chemokine ligand 20) promote T cell immunosuppression via programmed death-ligand 1 (PD-L1) in breast cancer. Issue 1 (1st January 2021)

• Record Type: Journal Article
• Authors: Kwantwi, Louis Boafo; Wang, Shujing; Zhang, Wenjun; Peng, Weidong; Cai, Zeyu; Sheng, Youjing; Xiao, Han; Wang, Xian; Wu, Qiang
• Is Part Of: Bioengineered. Volume 12:Issue 1(2021)
• Page Start: 6996
• Page End: 7006
• Publication Date: 2021-01-01
• Subjects: Tumor-associated neutrophils -- CCL20 -- PD-L1 -- immunosuppressive -- breast cancer; Biomedical engineering -- Periodicals; Biotechnology -- Periodicals; Microbiology -- Periodicals; 660.6
• DOI: 10.1080/21655979.2021.1977102
• Languages: English
• ISSNs: 2165-5987

Abstract

ABSTRACT: Breast cancer is the leading cause of cancer-related death among women despite the significant improvement in diagnosis and treatment. Tumor-associated neutrophils have been shown to suppress antitumor functions of the host. However, how breast cancer tumor microenvironment influences the phenotype and functions of neutrophils to potentiate T cell immunosuppression is unknown. Herein, neutrophils isolated from peripheral blood of healthy donors were treated with supernatants from breast cancer cell lines or recombinant human CCL20. PD-L1 expression on neutrophils was then evaluated by immunofluorescence and flow cytometry. Neutrophils and Jurkat T cells were cocultured to evaluate the effect of tumor-associated neutrophils on T cell functions. Finally, immunohistochemical staining was performed to evaluate the clinical relevance of neutrophils infiltrating breast tumor tissues. Tumor-derived CCL20 activated and upregulated PD-L1 expression on neutrophils. A significant positive correlation was found between CCL20 and CD66b+ neutrophils in tumor tissues. Through in vitro experiment, tumor-associated neutrophils (TANs) effectively suppressed T cell immunity which was reversed upon PD-L1 blockade. Moreover, a high density of TANs was associated with short disease free survival in breast cancer patients. Furthermore, receiver operating curve showed that the density of TANs could accurately predict disease-free survival in breast cancer patients. Our findings suggest that targeting TANs via CCL20 immunosuppressive pathway may be a novel therapeutic strategy for breast cancer treatment.