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Cancer Immunol Res. 2017 Apr;5(4):330-344. doi: 10.1158/2326-6066.CIR-16-0182. Epub 2017 Mar 6.

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

Author information

1
Georgia Cancer Center, Augusta University, Augusta, Georgia.
2
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia.
3
Verna and Marrs Mclean Department of Biochemistry, Baylor College of Medicine, Houston, Texas.
4
Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University, Augusta, Georgia.
5
Department of Statistics, Sungkyunkwan University, Seoul, South Korea.
6
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
7
Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia.
8
Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China.
9
Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida.
10
Department of Molecular and Cell Biology and Verna and Marrs Mclean Department of Biochemistry and Molecular Biology, Dan L. Duncan Cancer Center and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas.
11
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
12
Tianjing Medical University Cancer Institute and Hospital, Ministry of Education, Tianjin, China.
13
Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia.
14
Georgia Cancer Center, Augusta University, Augusta, Georgia. hshi@augusta.edu.

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 breast cancer 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 promoter methylation regulates anti-immune responses in breast cancer subtypes and could be used as a predictive biomarker for IDO1 inhibitor-based immunotherapy. Cancer Immunol Res; 5(4); 330-44. ©2017 AACR.

PMID:
28264810
PMCID:
PMC5493476
DOI:
10.1158/2326-6066.CIR-16-0182
[Indexed for MEDLINE]
Free PMC Article

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