title: Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers.
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.
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Huili
authors.initials: H
authors.lastname: Li
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Chiappinelli
authors.forename: Angela A
authors.initials: AA
authors.lastname: Guzzetta
authors.forename: Hariharan
authors.initials: H
authors.lastname: Easwaran
authors.forename: Ray-Whay Chiu
authors.initials: RW
authors.lastname: Yen
authors.forename: Rajita
authors.initials: R
authors.lastname: Vatapalli
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Topper
authors.forename: Jianjun
authors.initials: J
authors.lastname: Luo
authors.forename: Roisin M
authors.initials: RM
authors.lastname: Connolly
authors.forename: Nilofer S
authors.initials: NS
authors.lastname: Azad
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Nancy
authors.initials: N
authors.lastname: Davidson
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Zahnow
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
mesh_terms: D001374:Azacitidine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000276:immunology*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology*
chemical_list: D004273:DNA, Neoplasm; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine