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 anti-tumor immune responses. However, given the reported association of miR-155 to 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 cancer cell-derived miR-155, on anti-tumor 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 anti-tumor 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 pSTAT1/pSTAT3 ratio. We further found that serum miR-155 levels in breast cancer patients correlate 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 therapeutic elevation of miR-155 in breast tumors may improve the efficacy of ICB therapy via remodeling the anti-tumor immune landscape.

Harnessing tumorous flaws for immune supremacy: is miRNA-155 the weak link in breast cancer progression?

“…Utilizing publicly available TCGA data, Wang et al ( 7 ) confirmed that miR-155 levels are upregulated in breast cancer patients and positively correlated with overall patient survival ( Figure 1 ). Moreover, patients with stage I/II breast cancer and those without lymph node involvement had higher miR-155 levels than patients with advanced cancer stages and those with lymph node metastasis, respectively.…”

“…However, a critical question remains: Can we utilize the miRNAs to modulate immune function to address diseases affecting humans? To answer this question, Wang et al, in this issue of the JCI , have attempted to understand the antitumor role of one such oncomiR, miR-155, in breast cancer and its potential in harnessing the efficacy of immune checkpoint blockade (ICB) therapy ( 7 ).…”

“…The marked knowledge gap in elucidating the role of miR-155 in breast cancer can be attributed to the in vitro models or immunodeficient animal models that lack fully functioning immune components. The syngeneic mouse models used by Wang et al overcome these limitations and provide an extensive understanding of the biological functions of miR-155 in breast cancer ( 7 ).…”

“…Interestingly, the elevated miR-155 levels in the tumor cells were sufficient to suppress tumor progression and metastasis, and miR-155 depletion in the tumor cells reversed the antitumor effects. These data indicated that miR-155 is important in regulating tumor progression, and its overexpression results in decreased tumor progression and suppression of metastasis ( 7 ). However, due to the lack of single-cell RNA-Seq data for human breast cancer tissues, it is unknown what the primary source of miR-155 is, whether there is altered miR-155 expression in tumor-associated stromal cells (fibroblasts, immune cells, and endothelial cells), and how it contributes to tumorigenesis in human breast cancer.…”

“…Compared with the control counterparts, higher expression levels of miR-155 downregulated suppressor of cytokine signaling 1 (SOCS1), increased the ratio of phosphorylated STAT1 (pSTAT1) to pSTAT3, and stimulated chemoattractants CXCL9, CXCL10, and CXCL11 for T cell activation and subsequent proimmune antitumor response. In human breast cancer, miR-155 levels were positively correlated with the presence of CD8 + T cells and M1 macrophages in the tumor microenvironment (TME), making it a fair case for exploring the importance of miR-155 in cancer immune regulation and its potential in cancer immunotherapy ( 7 ).…”