miR-18a Mediates Immune Evasion in ER-Positive Breast Cancer through Wnt Signaling.
Madhumathy G NairApoorva DChandrakala MSnijesh VpSharada PatilAnupama CeGeetashree MukherjeeRekha V KumarJyothi S PrabhuSridhar TsPublished in: Cells (2022)
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.
Keyphrases
- cell proliferation
- long non coding rna
- poor prognosis
- long noncoding rna
- breast cancer cells
- estrogen receptor
- endoplasmic reticulum
- signaling pathway
- stem cells
- induced apoptosis
- machine learning
- transcription factor
- positive breast cancer
- pi k akt
- adipose tissue
- bone marrow
- cell death
- cell cycle arrest
- binding protein
- anti inflammatory
- genome wide
- nk cells
- free survival
- ultrasound guided