Breast cancer cell–derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function
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
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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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 7

High miR-155 expression increases the level of immuno-break molecules and improves the tumor response to immunotherapy.

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High miR-155 expression increases the level of immuno-break molecules an...
(A) Multi-GSEA analysis showing the enrichment of negative immune response signatures in miR-155hi (n = 497) and miR-155lo (n = 498) human breast cancer tumors. (B) Box plot showing T cell exhaustive and immunosuppressive genes in miR-155hi (n = 497) and miR-155lo (n = 498) tumors. (C) Relative expression of T cell exhaustive and immunosuppressive genes in sorted tumor-infiltrating leukocytes from tumor-bearing mice. n = 6 per group. (D) Soluble PD-L1 concentration in TILs by ELISA. n = 6 per group. (E) Tumor growth curves of EO771-GFP or EO771-Bic tumors of mice treated with anti–PD-L1 mAbs. IgG2b was applied as isotype control. n = 7–10 per group. (F) Percentage of tumor inhibition at various time points after anti–PD-L1 mAb treatment. n = 7–9 per group. Statistical significance was assessed using 2-tailed Student’s t test for comparing 2 groups (F) and 1-way ANOVA followed by Tukey’s post hoc test for multiple groups (C and D). All data are represented as mean ± SEM. #P < 0.05 compared with WT counterparts; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.