Abstract
Dysregulation of the epigenome drives aberrant transcriptional programmes that promote cancer onset and progression. Although defective gene regulation often affects oncogenic and tumour-suppressor networks, tumour immunogenicity and immune cells involved in antitumour responses may also be affected by epigenomic alterations. This could have important implications for the development and application of both epigenetic therapies and cancer immunotherapies, and combinations thereof. Here, we review the role of key aberrant epigenetic processes — DNA methylation and post-translational modification of histones — in tumour immunogenicity, as well as the effects of epigenetic modulation on antitumour immune cell function. We emphasize opportunities for small-molecule inhibitors of epigenetic regulators to enhance antitumour immune responses, and discuss the challenges of exploiting the complex interplay between cancer epigenetics and cancer immunology to develop treatment regimens combining epigenetic therapies with immunotherapies.
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The authors declare the following competing interests: the Johnstone laboratory receives funding from Roche, BMS and MecRx. R.W.J is a paid consultant and shareholder of MecRx. M.A.D. has been a member of advisory boards for CTX CRC, Storm Therapeutics, Celgene and Cambridge Epigenetix. S.J.H. and R.W.J. are inventors on a patent (WO2017059319A3) related to combining bromodomain inhibitors and immune-modulating therapies.
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Glossary
- Enhancer
-
A distal cis-regulatory element that activates gene expression via long-range interactions with gene promoters. Active enhancers are identified by specific histone modifications (such as histone H3 acetylated at K27 (H3K27ac), histone H3 methylated at K4 (H3K4me1) and H3K4me2) and are occupied by transcriptional co-activators, including the Mediator complex, Bromodomain containing 4 (BRD4) and P300.
- Tumour microenvironment
-
(TME). The interacting local environment in which proliferating tumour masses grow, comprising non-tumour cells (such as stromal fibroblasts, immune cells and blood/lymphatic vascular networks), secreted factors and extracellular matrix proteins.
- Major histocompatibility complex
-
(MHC). A protein complex subdivided into class I and class II that functions to present antigenic peptides on the cell surface to CD8+ T cells and CD4+ T cells, respectively.
- Endogenous retroviruses
-
(ERVs). Retroviral sequences that have integrated into the genome of all vertebrates throughout the course of evolution, to now constitute approximately 8% of the modern human genome. Multiple epigenetic mechanisms are utilized to prevent active transcription of ERVs, including DNA and histone methylation.
- Viral mimicry
-
Transcription of human endogenous retroviruses, which are repressed under homeostatic conditions, can be interpreted by the cell as an active viral infection, triggering an innate immune response (termed viral mimicry), including the production of type I interferons.
- Transcription factors
-
Proteins that recognize and bind specific genomic DNA sequences (termed ‘motifs’) and regulate transcription. Although many are ubiquitously expressed, certain ‘lineage-specifying’ transcription factors are only expressed in a cell type-specific manner where they orchestrate transcriptional programmes that control cell state/differentiation/fate phenotypes.
- Interferons
-
A pleotropic family of cytokines comprising type I (IFNα/IFNβ), type II (IFNγ) and type III (IFNλ) interferons, secreted by various immune cell subsets, that evoke antiviral, antiproliferative and/or immunomodulatory effects, including promoting antigen presentation.
- Immune checkpoint
-
T cell activation is a finely controlled process that can be enhanced or repressed by receptor activation. Immune checkpoints, such as PD1, act to inhibit effector T cell functions through negative regulation of intracellular signalling pathways, which leads to T cell activation.
- Type 1 T helper
-
(TH1). CD4+T helper cells are subset into distinct lineages defined by distinct expression of master transcription factors and cytokines with each lineage. TH1 cells are defined by their expression of the transcription factor TBET and production of IFNγ and tumour necrosis factor (TNF). In the context of cancer immunity, TH1 cells are associated with antitumour immune responses.
- Positive transcription elongation factor b
-
(P-TEFb). A transcriptional co-activation complex comprising cyclin-dependent kinase 9 (CDK9) and cyclin T1, which phosphorylates RNA polymerase II to release it from the pause-release checkpoint and stimulate transcriptional elongation.
- Super-enhancers
-
Large cis-regulatory elements comprising clusters of individual enhancers that are thought to cooperatively regulate the expression of single genes. Genes regulated by super-enhancers are frequently master lineage-specifying transcription factors and other proteins integral for cell type specification.
- Exhaustion
-
A state of dysfunction that in T cells arises from chronic stimulation through antigen persistence, such as in chronic viral infection or cancer. It is associated with increased expression of inhibitory cell surface receptors and an inability to express key effector genes required for T cell activation.
- Chimeric antigen receptor T cell
-
(CAR T cell). A form of adoptive cellular therapy where a patient’s own T cells are transduced to express a synthetic CAR in which the extracellular region binds to a defined tumour antigen and the intracellular domain contains the signalling moieties of CD3ζ and CD28 or 4-1BB. Activation of the CAR T cell therefore leads to potent T cell activation and cytotoxic activity directed towards the tumour cell.
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Hogg, S.J., Beavis, P.A., Dawson, M.A. et al. Targeting the epigenetic regulation of antitumour immunity. Nat Rev Drug Discov 19, 776–800 (2020). https://doi.org/10.1038/s41573-020-0077-5
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DOI: https://doi.org/10.1038/s41573-020-0077-5
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