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.

Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model

“…Of the cancers investigated to date, this effect is most pronounced in ovarian cancer cells (16). Treatment of ovarian cancer cells with the DNA methyltransferase inhibitor DAC (17) results in expression of cancer-testis antigens and MHC class I, increasing cancer cell recognition by CD8 þ T cells (18).…”

Global methylation and promoter-specific methylation of the P16, SOCS-1, E-cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission

“…This results in gene silencing and has been associated with cancer development through the inactivation of tumor suppressor genes (10)(11)(12)(13)(14)(15)(16). Unlike DNA sequence alterations, epigenetic modifications, such as DNA methylation, are dynamic and reversible with proven therapeutic implications (17)(18)(19). Furthermore, this method of deregulating functional pathways is more straightforward and therefore Global methylation and promoter-specific methylation of the P16, SOCS-1, E-cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission more likely to be effective than generating mutations or chromosomal aberrations (17).…”

Unraveling the molecular pathways of DNA-methylation inhibitors: human endogenous retroviruses induce the innate immune response in tumors

“…1 Current data has also shown that epigenetic therapies, including the DNA-methylation inhibitors 5-Azacytidine (Aza) and 5-Aza-2 0 -deoxycytidine (5-Aza-dC) (Decitabine), boost immune signaling of tumor cells. 2,3 Therefore, cancer treatments combining inhibition of DNA methylation with blockage of immune checkpoint proteins are a promising new therapeutic direction. Two recent publications shed light on the basic molecular and cellular efficacy regarding the above therapies, 3,4 where one common link implicates the innate immune system.…”