Breast cancer cell–derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function
Junfeng Wang, … , Guoshuai Cai, Daping Fan
Junfeng Wang, … , Guoshuai Cai, Daping Fan
Published August 4, 2022
Citation Information: J Clin Invest. 2022;132(19):e157248. https://doi.org/10.1172/JCI157248.
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Breast cancer cell–derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function

Abstract

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 bioinformatic 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 miR-155 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.

Authors

Junfeng Wang, Quanyi Wang, Yinan Guan, Yulu Sun, Xiaozhi Wang, Kaylie Lively, Yuzhen Wang, Ming Luo, Julian A. Kim, E. Angela Murphy, Yongzhong Yao, Guoshuai Cai, Daping Fan

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Figure 3

miR-155 expression levels in breast tumors are positively correlated with antitumor immunity.

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miR-155 expression levels in breast tumors are positively correlated wit...
(A) Volcano plot for the DEGs in miR-155hi versus miR-155lo tumors. P adj, adjusted value. (B) Multi-GSEA analysis of immune-related gene signatures in miR-155hi versus miR-155lo tumors. (C) Box plots comparing T cell–associated gene expression between miR-155hi (n = 497) and miR-155lo (n = 498) tumors. (D) Correlations of normalized miR-155 expression with predicted immune cell fractions in breast cancer tumors. n = 995. (E) Representative H&E staining and computational staining images of breast cancer tumors from TCGA, which were retrieved from the CANCER Digital Slide Archive and TCIA, respectively. Normalized miR-155 expression and TIL percentage values are shown above corresponding images. (F) Quantification of estimated TIL proportions in miR-155hi and miR-155lo breast cancer tumors. n = 432 per group. (G) Correlations of miR-155 levels with the percentages of TILs in breast cancer tumor tissues. n = 864. (C) Wilcoxon’s rank sum test was carried out to compare T cell activation–related gene expression between miR-155hi and miR-155lo breast cancer tumors. ***P < 0.001. (D and G) P and r value were calculated based on Pearson’s correlation analysis. (F) Statistical significance was assessed using unpaired, 2-tailed Student’s t test, and all data are represented as mean ± SEM. ****P < 0.0001.