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

摘要: // Huili Li 1,* , Katherine B. Chiappinelli Angela A. Guzzetta Hariharan Easwaran 1 Ray-Whay Chiu Yen Rajita Vatapalli Michael J. Topper Jianjun Luo Roisin M. Connolly 1,2 Nilofer S. Azad Vered Stearns Drew Pardoll Nancy Davidson 3 Peter Jones 4 Dennis Slamon 5 Stephen Baylin Cynthia Zahnow Nita Ahuja 1,6 Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 2 Breast Program, Medicine, University Pittsburgh Institute and UPMC CancerCenter, Pittsburgh, PA Departments Urology Biochemistry Molecular Biology, USC Norris Center, Keck School Southern California, Los Angeles, CA Jonsson California-Los Angeles 6 Surgery, Hopkins University, * These authors contributed equally to the work Correspondence: Ahuja, email: Zahnow, Keywords : Epigenetics, immune, cancers, DNA methyltransferase inhibitor, interferon, methylation, antigen processing Received February 4, 2014 Accepted 16, Published Abstract Epigenetic therapy is emerging as a potential for solid tumors. To investigate its mechanism action, we performed integrative expression methylation analysis 63 cancer cell lines (breast, colorectal, ovarian) after treatment with inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, presentation, cytokines/chemokines. Strong upregulation testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from union these pathway genes classified primary tumors types, into “high” “low” AIM subsets tumor data both TCGA GEO. Samples selected patient biopsies showed epigenetic therapy. results point broad immune stimulatory role demethylating drugs multiple cancers.