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

Abstract

Loss of DNA methylation can activate endogenous retroviral expression and dsRNA in cancer cells. This leads to induction of toll-like receptor signaling stimulating an antiviral interferon response. Recent findings provide a therapeutic rationale for combining DNA methylation inhibitors with blockage of immune checkpoint proteins to fight cancer.

Keywords: DNA methylation; IFN-signalling; TLR; dsRNA; endogeneous retrovirus (ERV); epigenetic therapy; immune checkpoints; innate immunity.

Figures

Figure 1.

Different exogenous and endogenous RNA species induce the innate immune system via TLR, RIG-I and MDA5 resulting in cytokine and interferon signaling. The main ERV RNA species inducing the immune response include dsRNA and ssRNA. RIG-I, retinoic acid inducible gene-1 (or RARRES3); MAVS, mitochondrial antiviral signaling protein (or IPS1); TLR, toll-like receptor; MyD88, myeloid differentiation primary response 88; MDA5, melanoma differentiation-associated 5 (or IFIH1); LGP2, laboratory of genetics and physiology 2 (or DHX58); TRIF, TIR domain-containing adaptor-inducing interferon-β (or TICAM1); NF-kB, nuclear factor kappa-light-chain-enhancer of activated B-cells; IRF, interferon regulatory factor; IFN, interferon.