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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 Article has an altmetric score of 4

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

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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 4

Forced miR-155 overexpression inhibits tumor growth by increasing immune cell influx.

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Forced miR-155 overexpression inhibits tumor growth by increasing immune...
(A) EO771-GFP and EO771-Bic tumor growth curves in WT or miR-155–KO mice. n = 10–20 per group. (B) EO771 tumor weight 29 days after tumor inoculation. n = 10 per group. (C) Frequency of tumor-infiltrating CD45+ leukocytes by flow cytometry. n = 6 per group. (D) Representative pseudo color images from 6 samples of each group showing the frequency of CD8+ T cells gating from CD45+ cells. (E) Quantified percentage of CD8+ T cells in EO771 tumors. (F) 4T1-GFP and 4T1-Bic tumor growth curves in BALB/c mice. 4T1 tumor weight (G) and CD45+ immune cell percentages (H) 19 days after tumor inoculation. (I) Representative pseudo color images showing the frequency of CD8+ T cells gating from CD45+ cells. (J) Quantified percentage of CD8+ T cells in 4T1 tumors. n = 10 per group (F–J). (K) T cell activation–related gene expression in sorted tumor-infiltrating CD45+ cells by qPCR. n = 6 per group. (L) Schematic image illustrating the procedure of TIF collection from tumor tissue and ELISA. IFN-γ (M) and TNF-α (N) protein concentrations in TIFs. Statistical analysis of A and F was performed using 2-way ANOVA followed by Tukey’s test. Statistical significance was assessed using 2-tailed Student’s t test for comparing 2 groups (G, H and J) and 1-way ANOVA followed by Tukey’s post hoc test for multiple groups (B, C, E, K, M, and N). 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.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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