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

190 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Azacitidine
Methyltransferases
DNA
Neoplasms
Antigen Presentation
Epigenomics
Genes
Up-Regulation
Therapeutics
Testicular Neoplasms
Chemokines
Interferons
Methylation
Breast
Cytokines
Biopsy
Gene Expression
Antigens
Cell Line
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. / Li, Huili; Chiappinelli, Katherine B.; Guzzetta, Angela A.; Easwaran, Hariharan; Yen, Ray Whay Chiu; Vatapalli, Rajita; Topper, Michael J.; Luo, Jianjun; Connolly, Roisin M.; Azad, Nilofer S.; Stearns, Vered; Pardoll, Drew M.; Davidson, Nancy; Jones, Peter A.; Slamon, Dennis J.; Baylin, Stephen B.; Zahnow, Cynthia A.; Ahuja, Nita.

In: Oncotarget, Vol. 5, No. 3, 2014, p. 587-598.

Research output: Contribution to journalArticle

Li, H, Chiappinelli, KB, Guzzetta, AA, Easwaran, H, Yen, RWC, Vatapalli, R, Topper, MJ, Luo, J, Connolly, RM, Azad, NS, Stearns, V, Pardoll, DM, Davidson, N, Jones, PA, Slamon, DJ, Baylin, SB, Zahnow, CA & Ahuja, N 2014, 'Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers', Oncotarget, vol. 5, no. 3, pp. 587-598. https://doi.org/10.18632/oncotarget.1782
Li, Huili ; Chiappinelli, Katherine B. ; Guzzetta, Angela A. ; Easwaran, Hariharan ; Yen, Ray Whay Chiu ; Vatapalli, Rajita ; Topper, Michael J. ; Luo, Jianjun ; Connolly, Roisin M. ; Azad, Nilofer S. ; Stearns, Vered ; Pardoll, Drew M. ; Davidson, Nancy ; Jones, Peter A. ; Slamon, Dennis J. ; Baylin, Stephen B. ; Zahnow, Cynthia A. ; Ahuja, Nita. / Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. In: Oncotarget. 2014 ; Vol. 5, No. 3. pp. 587-598.
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