Epigenetic therapy in immune-oncology

Abstract

DNA methylation inhibitors have become the mainstay for treatment of certain haematological malignancies. In addition to their abilities to reactivate genes, including tumour suppressors, that have acquired DNA methylation during carcinogenesis, they induce the expression of thousands of transposable elements including endogenous retroviruses and latent cancer testis antigens normally silenced by DNA methylation in most somatic cells. This results in a state of viral mimicry in which treated cells mount an innate immune response by turning on viral defence genes and potentially expressing neoantigens. Furthermore, these changes mediated by DNA methylation inhibitors can also alter the function of immune cells relevant to acquired immunity. Additionally, other inhibitors of epigenetic processes, such as histone deacetylases, methylases and demethylases, can elicit similar effects either individually or in combinations with DNA methylation inhibitors. These findings together with rapid development of immunotherapies open new avenues for cancer treatment.

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Fig. 1: Genome structure and activity of endogenous retroviruses.
Fig. 2: The viral mimicry state induced by epigenetic therapy.
Fig. 3: Increased tumour immunogenicity mediated by viral mimicry.
Fig. 4: Epigenetic reprogramming during CD8+ T cell dysfunction.

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Acknowledgements

This work was supported by National Cancer Institute Grant R35CA209859 to P.A.J. Research funding was also provided by Van Andel Research Institute through the Van Andel Research Institute – Stand Up To Cancer Epigenetics Dream Team. Stand Up To Cancer is a programme of the Entertainment Industry Foundation, administered by the American Association for Cancer Research (AACR). This work was supported by the Canadian Institutes of Health Research (CIHR) New Investigator Salary Award (201512MSH-360794-228629), a Helen M Cooke professorship from Princess Margaret Cancer Foundation, Canada Research Chair (950-231346), a CIHR Foundation Grant (FDN 148430) and the Ontario Institute for Cancer Research (OICR) with funds from the province of Ontario to D.D.D.C. A.C. is supported by The Guglietti Fellowship in Tumour Immune Therapy from the Princess Margaret Cancer Foundation.

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H.O. and A.C. researched the data for the article and provided a substantial contribution to discussions of the content. P.A.J. and D.D.D.C. contributed equally to writing the article and to the review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Daniel D. De Carvalho.

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Competing interests

P.A.J. is a consultant for Zymo Inc. D.D.D.C. receives research funding from Nektar Therapeutics. H.O. and A.C. declare no competing interests.

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Glossary

CpG sites

CpG is the contraction for 5'-C-phosphate-G-3'. CpG sites are DNA coordinates where a cytosine is immediatelly followed by a guanine in the 5' to 3' direction.

Transposable elements

Repetitive sequences that make up >40% of the human genome. They consist of three broad classes: endogenous retroviruses (ERVs), short interspersed nuclear elements (SINEs), of which the Alu elements are a major class, and long interspersed nuclear elements (LINEs).

Cancer–testis antigens

(CTAs). A category of antigens with normal expression restricted mainly to male germ cells in the testis, an immune-privileged organ. CTAs are frequently expressed in cancer cells.

Endogenous retroviruses

(ERVs). Endogenous viral elements in the genome that are acquired when retroviruses infect germ cells during evolution. ERVs are a class of transposable element.

Histone deacetylase

A class of enzyme that removes the acetyl groups on histones, reducing gene expression; inhibitors of histone deacetylases increase levels of acetylation and therefore expression.

Synthetic lethality

A process by which the simultaneous perturbation of two genes results in cellular death but the perturbation of each gene individually does not.

Bioavailability

The proportion of the administered drug that is able to have an active effect.

Bromodomain and extraterminal inhibitors

(BET inhibitors). Molecules able to inhibit protein–protein interactions between BET proteins, such as bromodomain-containing protein 2 (BRD2), BRD3 and BRD4, and acetylated histones and transcription factors.

Class I transactivator

A protein, such as NLRC5, which transcriptionally activates major histocompatibility complex (MHC) class I genes in a manner analogous to the MHC class II transactivator CIITA. In addition to MHC class I genes, NLRC5 can also induce the expression of other components of MHC class I antigen processing and presentation, such as β2-microglobulin (β2m), transporter involved in antigen processing 1 (TAP1) and LMP2 (also known as PSMB9).

Memory precursor effector T cells

A precursor subset of CD8+ T cells responsible for maintaining long-term immunological memory as well as for orchestrating rapid responses to cognate major histocompatibility complex (MHC) class I-restricted antigens. Naive CD8+ T cells undergo a cascade of differentiation that generates short-lived effector T cells and memory precursor effector T cells that then differentiate into long-lived memory T cells.

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Jones, P.A., Ohtani, H., Chakravarthy, A. et al. Epigenetic therapy in immune-oncology. Nat Rev Cancer 19, 151–161 (2019). https://doi.org/10.1038/s41568-019-0109-9

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