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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Research Article Immunology

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 6

miR-155 KO in EO771 cells promotes tumor growth by impairing antitumor immune infiltration.

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miR-155 KO in EO771 cells promotes tumor growth by impairing antitumor i...
(A) Validation of miR-155 expression in miR-155–KO EO771 cells by qPCR. n = 3 per group. Representative pseudo color image (B) and quantified data (C) showing percentage of Brdu+ control and miR-155–KO EO771 cells. n = 3 per group. (D) Ccl5 and Cxcl9/10/11 expression in control and miR-155–KO EO771 cells by qPCR. n = 3 per group. Representative histograms (E) and quantified MFI (F) of intracellular CXCL9 in control and miR-155–KO EO771 cells by flow cytometry. n = 5 per group. (G) EO771-control and EO771-miR-155–KO tumor growth curves in WT mice. n = 10 per group. (H) Tumor weight 19 days after tumor inoculation. n = 10 per group. (I) Frequency of tumor-infiltrating CD45+ leukocytes by flow cytometry. n = 5 per group. (J) Representative pseudo color images from 5 samples of each group showing the frequency of CD8+ T cells gating from CD45+ cells. Quantified percentage of CD8+ (K) and IFN-γ+CD8+ (L) T cells in tumors. (M) Representative Western blotting bands showing SOCS1 protein and STAT1/STAT3 protein and phosphorylation levels in EO771-control and EO771-miR-155–KO cells. For samples run on different gels, separate loading controls are provided in the supplemental material. (N) Blots shown in M were quantified relative to β-actin expression. n = 3 per group. (O) The ratio of p-STAT1 to p-STAT3 in EO771-control and EO771-miR-155–KO cells based on band intensity. n = 3 per group. Statistical significance in all figures was assessed using the unpaired, 2-tailed Student’s t test. All data are represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.