title: 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 moreIDO1than MCF7 cells. The two cell lines had similar upstream JAK/STAT1 signaling andIDO1mRNA 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 ofIDO1expression in MCF7 cells, suggesting that DNA methylation was potentially involved inIDO1induction. By analyzing several breast cancer datasets, we discovered subtype-specific mRNA and promoter methylation differences inIDO1, with TNBC/basal subtypes exhibiting lower methylation/higher expression and ER+/luminal subtypes exhibiting higher methylation/lower expression. We confirmed this trend ofIDO1methylation by bisulfite pyrosequencing breast cancer cell lines and an independent cohort of primary breast tumors. Taken together, these findings suggest thatIDO1promoter 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.
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Noonepalle
authors.affiliation: Verna and Marrs Mclean Department of Biochemistry, Baylor College of Medicine, Houston, Texas.
authors.forename: Franklin
authors.initials: F
authors.lastname: Gu
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Eun-Joon
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Qimei
authors.initials: Q
authors.lastname: Han
authors.affiliation: Department of Statistics, Sungkyunkwan University, Seoul, South Korea.
authors.forename: Jaejik
authors.initials: J
authors.lastname: Kim
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Maria
authors.initials: M
authors.lastname: Ouzounova
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Austin Y
authors.initials: AY
authors.lastname: Shull
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Lirong
authors.initials: L
authors.lastname: Pei
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Pei-Yin
authors.initials: PY
authors.lastname: Hsu
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kolhe
authors.affiliation: Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Fang
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Jiseok
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Katie
authors.initials: K
authors.lastname: Chiou
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Hasan
authors.initials: H
authors.lastname: Korkaya
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Xin
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
authors.affiliation: 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.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Tianjing Medical University Cancer Institute and Hospital, Ministry of Education, Tianjin, China.
authors.forename: Shou-Ching
authors.initials: SC
authors.lastname: Tang
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia. hshi@augusta.edu.|Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D019175:DNA Methylation; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality
chemical_list: D016207:Cytokines; C576710:IDO1 protein, human; C494257:IRF1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050856:Interferon Regulatory Factor-1; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D053612:Janus Kinases