Epigenetics and immunotherapy: The current state of play

Abstract

Cancer cells employ a number of mechanisms to escape immunosurveillance and facilitate tumour progression. The recent explosion of interest in immunotherapy, especially immune checkpoint blockade, is a result of discoveries about the fundamental ligand-receptor interactions that occur between immune and cancer cells within the tumour microenvironment. Distinct ligands expressed by cancer cells engage with cell surface receptors on immune cells, triggering inhibitory pathways (such as PD-1/PD-L1) that render immune cells immunologically tolerant. Importantly, recent studies on the role of epigenetics in immune evasion have exposed a key role for epigenetic modulators in augmenting the tumour microenvironment and restoring immune recognition and immunogenicity. Epigenetic drugs such as DNA methyltransferase and histone deacetylase inhibitors can reverse immune suppression via several mechanisms such as enhancing expression of tumour-associated antigens, components of the antigen processing and presenting machinery pathways, immune checkpoint inhibitors, chemokines, and other immune-related genes. These discoveries have established a highly promising basis for studies using combined epigenetic and immunotherapeutic agents as anti-cancer therapies. In this review, we discuss the exciting role of epigenetic immunomodulation in tumour immune escape, emphasising its significance in priming and sensitising the host immune system to immunotherapies through mechanisms such as the activation of the viral defence pathway. With this background in mind, we highlight the promise of combined epigenetic therapy and immunotherapy, focusing on immune checkpoint blockade, to improve outcomes for patients with many different cancer types.

Epigenomics of mammary gland development

“…Epigenetic drugs do not only target the epithelial cells intrinsically but can also target the cross-talk between the epithelial cells and stromal cells. It has recently been shown that epigenetic therapies can sensitise cancer cells to the host immune system and boost the effects of immunotherapies such as check-point inhibitors (reviewed in [79]). This is particularly relevant to breast cancer, where treatment with check-point inhibitors has been shown to have limited efficacy compared with other cancer types [80].…”

Epigenetics in Melanoma Development and Drug Resistance

“…In melanoma, one clinical trial is currently investigating the combination of the BRAF/MEK inhibitors vemurafenib and cobimetinib with the DNA hypomethylating agent decitabine (NCT01876641). However, the main focus in the field appears to be the combination of epigenetic drugs, especially DNA methyltransferase and histone deacetylase inhibitors with immunotherapy, which is currently tested in numerous clinical trials [107] and the outcome of these promising approaches is highly anticipated.…”

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…Conversely, IDO1 inhibitors improved their efficacy when administered in combination with radiopharmaceutical drugs, cytotoxic anticancer agents, and so forth . Recent evidence showed that HDACi could be able to reverse immune suppression inducing an improvement in tumor recognition . Fang et al reported the first dual HDAC/IDO1 inhibitors, designed by insertion of the benzamide anti‐HDAC moiety of entinostat 9 or mocetinostat 10 into the structure of epacadostat 74 , through replacement in its molecule of the aminoethyl‐sulfamide function, exposed to the solvent in the binding with the enzyme .…”