Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers

Huili Li, Katherine B. Chiappinelli, Angela A. Guzzetta, Hariharan Easwaran, Ray Whay Chiu Yen, Rajita Vatapalli, Michael J. Topper, Jianjun Luo, Roisin M. Connolly, Nilofer S. Azad, Vered Stearns, Drew M. Pardoll, Nancy Davidson, Peter A. Jones, Dennis J. Slamon, Stephen B. Baylin, Cynthia A. Zahnow, Nita Ahuja

Research output: Contribution to journalArticle

221 Scopus citations

Abstract

Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and presentation, and cytokines/chemokines. Strong upregulation of cancer testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from the union of these immunomodulatory pathway genes classified primary tumors from all three types into "high" and "low" AIM gene expression subsets in tumor expression data from both TCGA and GEO. Samples from selected patient biopsies showed upregulation of AIM genes after treatment with epigenetic therapy. These results point to a broad immune stimulatory role for DNA demethylating drugs in multiple cancers.

Original languageEnglish (US)
Pages (from-to)587-598
Number of pages12
JournalOncotarget
Volume5
Issue number3
DOIs
StatePublished - 2014

Keywords

  • Antigen processing
  • Cancers
  • DNA methyltransferase inhibitor
  • Epigenetics
  • Immune
  • Interferon
  • Methylation

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Li, H., Chiappinelli, K. B., Guzzetta, A. A., Easwaran, H., Yen, R. W. C., Vatapalli, R., Topper, M. J., Luo, J., Connolly, R. M., Azad, N. S., Stearns, V., Pardoll, D. M., Davidson, N., Jones, P. A., Slamon, D. J., Baylin, S. B., Zahnow, C. A., & Ahuja, N. (2014). Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget, 5(3), 587-598. https://doi.org/10.18632/oncotarget.1782