Epigenetic Drugs and Their Immune Modulating Potential in Cancers

Abstract

Epigenetic drugs are used for the clinical treatment of hematologic malignancies; however, their therapeutic potential in solid tumors is still under investigation. Current evidence suggests that epigenetic drugs may lead to antitumor immunity by increasing antigen presentation and may enhance the therapeutic effect of immune checkpoint inhibitors. Here, we highlight their impact on the tumor epigenome and discuss the recent evidence that epigenetic agents may optimize the immune microenvironment and promote antiviral response.

Keywords: antiviral response; epigenetic drugs; epigenetics.

Figure 1

Principles of cancer epigenetic modifications and their drug targets. DNA methyltransferases (DNMTs) add methyl groups to DNA and maintain methylated DNA, while Tet methylcytosine dioxygenase 2 (TET2) removes the methyl groups from DNA. DNA methylation at the gene promoter impairs local binding of transcription factors and blocks transcription. Recruitment of methyl CpG binding domain (MBD) protein by the methylated DNA facilitates the heterochromatin formation and results in transcription repression. DNMT inhibitors such as decitabine and azacytidine will incorporate into the genome and degrade the activity of DNMT, reverse the aberrant DNA hypermethylation, and enable the re-expression of silenced genes. H3K9me3 and H3K27me3 serve as repressive histone marks, while H3K4me3 and H3K36me3 are active marks. Histone deacetylation is among the major repressive mechanisms of histone modification. Histone deacetylases (HDAC) inhibitors (e.g., vorinostat and romidepsin) inhibit histone deacetylation caused by HDAC to maintain active chromatin status for transcription. Me: DNA methylation; Ac: histone acetylation.

Figure 2

Transposable elements determine the inherent immunogenicity and response of tumor cells to epigenetic agents. Transposable elements (TE) in the genome are typically not actively transcribed but can be stimulated by stress and epigenetic agents. Endogenous retroviruses (ERVs) compose a major part of TE. Regionally hypermethylated ERVs are transcriptionally inactive, and repressive histone modifications at ERVs loci disturb the access of genome for transcription factors (TF). Epigenetic agents potentiate the transcription of ERVs into nucleic acids that mimic a virus infection. The transcription product of ERVs, dsRNA, are sensed by cytosolic sensors: retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5). The resulting signal is transduced by mitochondrial antiviral proteins (MAVs) and leads to NF-kb and interferon regulated factors (IRF) translocation into the nucleus, inducing the expression of interferon-stimulated genes (ISGs) and type I IFN response and results in tumor cell apoptosis or enhanced expression of tumor associated antigens. Hypomethylated ERVs may be a characteristic epigenetic feature in tumor cells and may perturb cellular responses to epigenetic agents. Inherent ERV patterns and regional epigenetic modifications may provide predictive value for epigenetic therapy [52,100,101].