Modulation of indoleamine expression by activated T-cells in breast cancer

All content on this webpage originated from other webpages,Please check the medicilon's website for details. Medicilon offers fully integrated pharmaceutical services for the global scientific community. We focus on providing an exceptional client-centered experience and advancing the drug discovery process.

Email: Marketing@medicilon.com.cn Website: www.medicilon.com

Tumor infiltrating lymphocytes (TILs) secrete cytokines that modulate immune responses at the tumor microenvironment. Tumor suppressor activity of interferon gamma (IFNγ) cytokine also activates protein expression of immune suppressive factors such as IDO and PD-L1 in tumor cells. However, there is still much to learn about how tumor cells counter the immune cells at the gene expression level. In this study, RNA-seq analysis of breast cancer cells after in-vitro co-culture with anti-CD3/CD28 activated human T-cells revealed that the IFNγ induced immune response gene signature is common to both triple negative breast cancer (TNBC) MDA-MB-231 and estrogen receptor positive (ER+) MCF7 cells. However, IDO1 expression was differentially upregulated with significantly higher expression in MDA-MB-231 compared to MCF7 cells. Analysis of the TCGA breast invasive carcinoma dataset revealed subtype specific mRNA expression and IDO1 promoter DNA methylation. We observed that IDO1 mRNA expression and promoter methylation followed inverse correlation. TNBC/Basal subtype was hypomethylated at the IDO1 promoter with higher mRNA expression compared to the ER+ subtype that was hypermethylated with relatively lower IDO1 mRNA expression. The IDO1 promoter methylation was confirmed by pyrosequencing analysis of a panel of breast cancer cell lines and patient tumors. IFNγ treatment of MDA-MB-231 and MCF7 breast cancer cells revealed no difference in terms of upstream signaling and IDO1 mRNA stability. Treatment with demethylating agent, 5-aza deoxycytidine, synergistically up-regulated IDO1 mRNA expression in ER+ MCF7 cells highlighting that CpG methylation controls IDO1 gene expression. We also found a positive correlation between IDO1 and CD8A expression and better relapse free survival in TNBC/basal subtype patients suggesting that IDO1 protein expression is driven by intrinsic immune surveillance of TILs. These findings provide evidence that IDO1 promoter methylation regulates anti-immune responses by tumor cells towards TILs and it could be used as a predictive biomarker for IDO inhibitor-based immunotherapy of breast cancer.