Immunological Effects of Epigenetic Modifiers

Abstract

Epigenetic alterations are associated with major pathologies including cancer. Epigenetic dysregulation, such as aberrant histone acetylation, altered DNA methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. Targeting epigenetic cancer hallmarks can be harnessed as an immunotherapeutic strategy, exemplified by the use of pharmacological inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) that can result in the release from the tumor of danger-associated molecular patterns (DAMPs) on one hand and can (re-)activate the expression of tumor-associated antigens on the other hand. This finding suggests that epigenetic modifiers and more specifically the DNA methylation status may change the interaction of chromatin with chaperon proteins including HMGB1, thereby contributing to the antitumor immune response. In this review, we detail how epigenetic modifiers can be used for stimulating therapeutically relevant anticancer immunity when used as stand-alone treatments or in combination with established immunotherapies.

Keywords: cancer; epigenetic modifiers; immunogenicity.

Figure 1

Epigenetic modifications occur at several levels including transcription, translation, splicing, and nuclear RNA release. Several mechanisms are considered to induce epigenetic changes, such as DNA methylation, histone modification, and non-coding RNA-associated gene silencing. Epigenetic modifiers from the group of histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) can (partially) revert such changes with multiple effects on tumors and the immune system.

Figure 2

Epigenetic modifiers from the group of histone deacetylase inhibitors (HDACi) affect the accessibility of chromatin and therefore impact on transcription. HDACi induce the release and exposure at the cellular surface of danger-associated molecular patterns (DAMPs) such as high mobility group box 1 (HMGB1), calreticulin (CALR), heat shock protein 70 (HSP70), and a range of chemokines. In addition, the expression of KLRK1 (better known as NKG2D) ligands and major histocompatibility complex (MHC) is increased. DNA methyltransferase inhibitors (DNMTi) affect the antigenicity of tumors by the de novo expression of cancer testis antigens, the availability of MHC molecules, and the concomitant release of chemokines. Independent from tumor specific effects, epigenetic modifiers also exert direct stimulatory effects on immune cells, including macrophages and T cells. Altogether, a combination treatment employing epigenetic modifiers together with immune checkpoint targeting might potentiate the immune response against cancer.