Promoter methylation modulates indoleamine 2,3-dioxygenase 1 induction by activated T cells in human breast cancers

Satish K. Noonepalle, Franklin Gu, Eun Joon Lee, Jeong Hyeon Choi, Qimei Han, Jaejik Kim, Maria Ouzounova, Austin Y. Shull, Lirong Pei, Pei Yin Hsu, Ravindra Kolhe, Fang Shi, Jiseok Choi, Katie Chiou, Tim H.M. Huang, Hasan Korkaya, Libin Deng, Hong Bo Xin, Shuang Huang, Muthusamy ThangarajuArun Sreekumar, Stefan Ambs, Shou Ching Tang, David H. Munn, Huidong Shi

Research output: Contribution to journalArticle

8 Scopus citations

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 lineMCF7 after both were cocultured with activated human T cells. Despite similarities in the cytokineinduced 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 IDO1methylation 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.

Original languageEnglish (US)
Pages (from-to)330-344
Number of pages15
JournalCancer Immunology Research
Volume5
Issue number4
DOIs
Publication statusPublished - Apr 2017

    Fingerprint

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this