M. Nair (Bangalore, India)

St Johns Research Institute

Author Of 2 Presentations

38P - Triple negative breast cancers with expression of Glucocorticoid receptor in immune cells show better prognosis

Abstract

Background

Glucocorticoid receptor (GR) is shown to have variable frequency of expression in invasive tumors of the breast. Investigation of additional nuclear receptors like GR in receptor negative tumors like triple negative breast cancer (TNBC) may have prognostic and therapeutic significance.

Methods

Expression of GR was evaluated by immunohistochemistry in 175 tumors of invasive breast cancer with long term follow up. GR Expression was separately evaluated in invasive tumor cells, stromal cells and tumor infiltrating lymphocytes (TIL’s). Staining pattern was categorised as positive when more than 1% of the cells stained in each subpopulation of cells. Disease free survival was analysed between GR positive and negative status by Kaplan Meier analysis.

Results

Of the 175 tumors, 121 (70%) were ER positive, 53 (30%) were ER negative and 29% (51) were triple negative. 74% (130/175) tumors showed expression of GR in invasive tumor cells while (84%) 147/175 had expression in TIL’s. No significant difference in distribution of GR was noted between ER positive and ER negative tumors (78% vs 66%, p-0.1). Of the TNBC’s 54% (28/51) and 70% (36/51) showed expression of GR in invasive tumor and TIL’s respectively. Overall, GR positive tumors had significant better survival than GR negative tumors (mean survival time of 85 vs 59 months respectively, p-0.04) Contrary to the reports that GR expression in TIL’s are associated with immunosuppressive activity in model systems, TNBC’s with increased expression of GR in immune cells were associated with better survival (Mean survival time 74 vs 41 months, log rank test- p-0.03). TNBC tumors which were GR negative had higher lymph node metastases (p-0.04) and none of the other clinical features like age, menopausal state, tumor size and grade were different between GR positive and negative tumors within TNBC.

Conclusions

Glucocorticoids (GC) are often used to alleviate the adverse symptoms during chemotherapy. Determining the GR status is of importance due to the pro cell survival effect of the glucocorticoids mediated through GR during chemotherapy. Though GC mediated effects on chemotherapy are controversial, our results indicate favourable effects in TNBC.

Legal entity responsible for the study

The authors.

Funding

Department of Biotechnology Wellcome Trust India Alliance.

Disclosure

All authors have declared no conflicts of interest.

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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.

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Presenter 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.

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