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.
View: Text | PDF
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

×

Figure 8

Circulating miR-155 mirrors antitumor immune status within breast tumors.

Options: View larger image (or click on image) Download as PowerPoint
Circulating miR-155 mirrors antitumor immune status within breast tumors...
(A) Relative miR-155 expression in serum collected from both WT and miR-155–KO mice carrying EO771-GFP or EO771-Bic tumors. n = 4 per group. Statistical significance was assessed using unpaired, 2-tailed Student’s t test, and all data are represented as mean ± SEM. *P < 0.05, ***P < 0.001. (B) Correlation between serum miR-155 levels measured by qPCR and the frequency of CD8+ T cells in tumors determined by flow cytometry. n = 12. (C–F) Correlation between serum miR-155 levels and CCL5 (C), CXCL9 (D), IL-12 (E), and soluble PD-L1 (F) concentrations in TIFs. n = 12. In a small cohort of human breast cancer samples, the expression of miR-155 and hallmark genes of T cell activation in serum, nontumor, and tumor tissues was determined by qPCR. (G) Schematic image showing the procedure of sampling from breast cancer patients. (H) Correlation between serum miR-155 levels and tumor tissue miR-155 expression. n = 29. (I–L) Correlations between serum miR-155 levels and mRNA levels of IL2 (I), CD8A (J), IFNG (K), and CD274 (L) in human breast cancer tumor tissues. n = 26. Pand r values in B–L were calculated based on Pearson’s correlation analysis.