Promoter Methylation Modulates Indoleamine 2,3-Dioxygenase 1 Induction by Activated T Cells in Human Breast Cancers

Abstract

Triple-negative breast cancer (TNBC) cells are modulated in reaction to tumor-infiltrating lymphocytes. However, their specific responses to this immune pressure are unknown. In order to address this question, we first used mRNA sequencing to compare the immunophenotype of the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were cocultured with activated human T cells. Despite similarities in the cytokine-induced immune signatures of the two cell lines, MDA-MD-231 cells were able to transcribe more IDO1 than MCF7 cells. The two cell lines had similar upstream JAK/STAT1 signaling and IDO1 mRNA stability. However, using a series of BC cell lines, IFNγ stimulated IDO1 protein expression and enzymatic activity only in ER−, not ER+, cell lines. Treatment with 5-aza-deoxycytidine reversed the suppression of IDO1 expression in MCF7 cells, suggesting that DNA methylation was potentially involved in IDO1 induction. By analyzing several breast cancer datasets, we discovered subtype-specific mRNA and promoter methylation differences in IDO1, with TNBC/basal subtypes exhibiting lower methylation/higher expression and ER+/luminal subtypes exhibiting higher methylation/lower expression. We confirmed this trend of IDO1 methylation by bisulfite pyrosequencing breast cancer cell lines and an independent cohort of primary breast tumors. Taken together, these findings suggest that IDO1 methylation regulates anti-immune responses in breast cancer subtypes and could be used as a predictive biomarker for IDO1 inhibitor–based immunotherapy.

Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophages

“…An immunomodulatory role for the enzyme indoleamine 2,3-dioxygenase (IDO), which catalyzes the conversion of tryptophan into kynurenine, has been suggested to have a role in macrophage functions 10 . Increased IDO activity is often associated with tumors and infectious diseases 11 . Several studies have described IDO-dependent T-cell suppression by antigen-presenting cells under many infectious and inflammatory conditions, indicating that biochemical changes due to tryptophan catabolism have a profound effect on T-cell proliferation and effector functions in tissue microenvironments 12 , 13 .…”

Mechanism and prognostic value of indoleamine 2,3‐dioxygenase 1 expressed in hepatocellular carcinoma

“…Notably, T‐IDO1 staining was not proportional to infiltrating CD8+ T cells some of the cases in our study, perhaps due to IDO1 also being constitutively expressed by tumor cells through poorly characterized oncogenic signaling pathways. Previous studies have revealed that intrinsic cellular changes triggered by poorly characterized genetic mutations and epigenetic modifications can also regulate T‐IDO1 expression; for example, either demethylated promoters or low expression of Bin1 could lead to highly inducible IDO1 expression in breast cancer . Both intrinsic and extrinsic mechanisms could be independently or jointly determining the T‐IDO1 level in the HCC microenvironment.…”

Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer

“…However, the molecular mechanisms that regulate IDO1 expression are not completely understood, including in esophageal cancer. Recently, it has been reported that IDO1 expression was regulated by promoter methylation in breast cancer . Promoter methylation is associated with gene expression levels and changes in transcriptional function or malignant behavior of cancer cells.…”