Breast cancer cell–derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function

• Published in: The Journal of clinical investigation 2022-10, Vol.132 (19), p.1-16
• Main Authors: Wang, Junfeng, Wang, Quanyi, Guan, Yinan, Sun, Yulu, Wang, Xiaozhi, Lively, Kaylie, Wang, Yuzhen, Luo, Ming, Kim, Julian A, Murphy, E. Angela, Yao, Yongzhong, Cai, Guoshuai, Fan, Daping
• Format: Article
• Language: English
• Subjects: Analysis; Antitumor activity; Biomedical research; Breast cancer; Carcinogenesis; Care and treatment; Clinical outcomes; Development and progression; Experiments; Gene expression; Genetic aspects; Genomes; Health aspects; Immune checkpoint; Immune response; Immune status; Immunology; Lymphatic system; Lymphocytes; Lymphocytes T; Medical prognosis; Metastasis; MicroRNA; MicroRNAs; miRNA; Patients; Stat1 protein; Stat3 protein; Tumorigenesis; Tumors
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI157248

Evidence suggests that increased microRNA-155 (miR-155) expression in immune cells enhances antitumor immune responses. However, given the reported association of miR-155 with tumorigenesis in various cancers, a debate is provoked on whether miR-155 is oncogenic or tumor suppressive. We aimed to interrogate the impact of tumor miR-155 expression, particularly that of cancer cell-derived miR-155, on antitumor immunity in breast cancer. We performed bioinformatics analysis of human breast cancer databases, murine experiments, and human specimen examination. We revealed that higher tumor miR-155 levels correlate with a favorable antitumor immune profile and better patient outcomes. Murine experiments demonstrated that miR-155 overexpression in breast cancer cells enhanced T cell influx, delayed tumor growth, and sensitized the tumors to immune checkpoint blockade (ICB) therapy. Mechanistically, miR-155 overexpression in breast cancer cells upregulated their CXCL9/10/11 production, which was mediated by SOCS1 inhibition and increased phosphorylated STAT1 (p-STAT1)/p-STAT3 ratios. We further found that serum miR-155 levels in breast cancer patients correlated with tumor miR155 levels and tumor immune status. Our findings suggest that high serum and tumor miR-155 levels may be a favorable prognostic marker for breast cancer patients and that therapeutic elevation of miR-155 in breast tumors may improve the efficacy of ICB therapy via remodeling the antitumor immune landscape.