S. Vp (Bangalore, India)
St. John's Research InstituteAuthor Of 1 Presentation
89P - High expression of miR-18a drives immunosuppressive activity in ER-positive breast cancer
Abstract
Background
Despite the successful use of checkpoint inhibitors in cancer immunotherapy, benefits in breast cancer have largely been confined to triple-negative cancers in the metastatic setting. ER-positive breast tumors which form the major subgroup of breast cancer are considered immunologically silent with few effector tumor-infiltrating lymphocytes (TILs). We have previously demonstrated high expression of miR-18a is associated with poor prognosis and its activation of Wnt signaling in ER-positive breast cancer. In this study, we have explored the modulation of the immune signature by miR-18a within ER-positive tumors.
Methods
miR-18a was overexpressed in MCF-7 cells using a synthetic mimic and a global gene expression pattern was arrived at by microarray experiments. Functional enrichment of differentially expressed genes (DEGs) was performed to identify the deregulated pathways. Further validation of the identified pathways was done in the TCGA cohort of ER-positive tumors with high expression of miR18a, by comparison between the tumors segregated based on upper and lower quartile of its expression. Immune cell identification was done using CIBERSORT analysis in these tumors.
Results
Functional enrichment of genes in MCF-7 cells with overexpression of miR-18a demonstrated dysregulation and suppression of immune-related pathways associated with TAP binding, HLA regulated genes with antigen binding, and interferon-gamma related signaling. Cytokine mediated signaling and response to cytokine-mediated signaling was also observed to be suppressed in these cells. Stratification of the ER+ tumor samples by miR-18a levels in the TCGA cohort revealed a higher proportion of resting macrophages (p<0.0001), T-regulatory cells (p=0.001), and resting Natural Killer Cells (p=0.041) in tumors expressing high levels of miR-18a. We also observed a lower proportion of monocytes (p=0.021) and a higher CD4/CD8 ratio (p=0.001) in these tumors.
Conclusions
Our results support the existence of an epigenetic mediated repression of the immune-related gene signature within ER-positive tumors. Immunomodulation brought about by the overexpression of miR-18a may contribute to immune suppression by evading the adaptive immune response in these tumors.
Legal entity responsible for the study
St. John's Research Institute.
Funding
Department of Health Research, Ministry of Health & Family Welfare, India Nadathur Estates.
Disclosure
All authors have declared no conflicts of interest.