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

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

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 int...

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Published in:The Journal of clinical investigation Vol. 132; no. 19; pp. 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: Journal Article
Language:English
Published: Ann Arbor American Society for Clinical Investigation 01-10-2022
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
China
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Summary: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.
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ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI157248