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miR-18a Mediates Immune Evasion in ER-Positive Breast Cancer through Wnt Signaling.
- Source :
- Cells (2073-4409); May2022, Vol. 11 Issue 10, p1672-N.PAG, 15p
- Publication Year :
- 2022
-
Abstract
- ER-positive (ER+) breast cancer is considered immunologically 'silent' with fewer tumor-infiltrating immune cells. We have previously demonstrated the role of miR-18a in mediating invasion and poor prognosis in ER+ breast cancer by activation of the Wnt signaling pathway. Here, we explored the immune-modulatory functions of high levels of miR-18a in these tumors. A microarray-based gene expression analysis performed in miR-18a over-expressed ER+ breast cancer cell lines demonstrated dysregulation and suppression of immune-related pathways. Stratification of the ER+ tumor samples by miR-18a levels in the TCGA and METABRIC cohort and immune cell identification performed using CIBERSORT and Immune CellAI algorithms revealed a higher proportion of T-regulatory cells (p < 0.001) and a higher CD4/CD8 ratio (p < 0.01). miR-18a over-expressed MCF7 co-cultured with THP-1 showed decreased antigen presentation abilities and increased invasiveness and survival. They also promoted the differentiation of pro-tumorigenic M2 macrophages. Inhibition of the Wnt pathway in miR-18a over-expressed cells brought about the restoration of TAP-1, a protein critical for antigen presentation. Examination of tumor specimens from our case series showed that miR-18a high ER+ tumors had a dense lymphocyte infiltrate when compared to miR-18a low tumors but expressed a higher CD4/CD8 ratio and the M2 macrophage marker CD206, along with the invasive marker MMP9. We report for the first time an association between miR-18a-mediated Wnt signaling and stromal immune modulation in ER+ tumors. Our results highlight the possibility of formulating specific Wnt pathway inhibitors that may be used in combination with immune checkpoint blockers (ICB) for sensitizing 'immune-cold' ER+ tumors to immunotherapy. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20734409
- Volume :
- 11
- Issue :
- 10
- Database :
- Complementary Index
- Journal :
- Cells (2073-4409)
- Publication Type :
- Academic Journal
- Accession number :
- 157146764
- Full Text :
- https://doi.org/10.3390/cells11101672