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Cell Commun Signal. 2017 Mar 31;15(1):13. doi: 10.1186/s12964-017-0168-z.

The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation.

Author information

1
Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
2
3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria.
3
Salzburg Cancer Research Institute - Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.
4
Cancer Cluster Salzburg, Salzburg, Austria.
5
3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria. l.pleyer@salk.at.
6
Salzburg Cancer Research Institute - Center for Clinical Cancer and Immunology Trials, Salzburg, Austria. l.pleyer@salk.at.
7
Cancer Cluster Salzburg, Salzburg, Austria. l.pleyer@salk.at.

Abstract

Hypomethylating agents (HMAs) have been widely used over the last decade, approved for use in myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The proposed central mechanism of action of HMAs, is the reversal of aberrant methylation in tumor cells, thus reactivating CpG-island promoters and leading to (re)expression of tumor suppressor genes. Recent investigations into the mode of action of azacitidine (AZA) and decitabine (DAC) have revealed new molecular mechanisms that impinge on tumor immunity via induction of an interferon response, through activation of endogenous retroviral elements (ERVs) that are normally epigenetically silenced. Although the global demethylation of DNA by HMAs can induce anti-tumor effects, it can also upregulate the expression of inhibitory immune checkpoint receptors and their ligands, resulting in secondary resistance to HMAs. Recent studies have, however, suggested that this could be exploited to prime or (re)sensitize tumors to immune checkpoint inhibitor therapies. In recent years, immune checkpoints have been targeted by novel therapies, with the aim of (re)activating the host immune system to specifically eliminate malignant cells. Antibodies blocking checkpoint receptors have been FDA-approved for some solid tumors and a plethora of clinical trials testing these and other checkpoint inhibitors are under way. This review will discuss AZA and DAC novel mechanisms of action resulting from the re-expression of pathologically hypermethylated promoters of gene sets that are related to interferon signaling, antigen presentation and inflammation. We also review new insights into the molecular mechanisms of action of transient, low-dose HMAs on various tumor types and discuss the potential of new treatment options and combinations.

KEYWORDS:

Acute myeloid leukemia; Azacitidine; Cancer; DNA methylation; Decitabine; Endogenous retroviral elements; Hypomethylating agents; Immune checkpoint blockade; Immune checkpoint inhibitors; Tumor microenvironment

PMID:
28359286
PMCID:
PMC5374693
DOI:
10.1186/s12964-017-0168-z
[Indexed for MEDLINE]
Free PMC Article

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