Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy

Abstract

The tumour microenvironment plays an instrumental role in cancer development, progression and treatment response/resistance. Accumulating evidence is underscoring the fundamental importance of epigenetic regulation in tumour immune evasion. Following many pioneering discoveries demonstrating malignant transformation through epigenetic anomalies ('epimutations'), there is also a growing emphasis on elucidating aberrant epigenetic mechanisms that reprogramme the milieu of tumour-associated immune and stromal cells towards an immunosuppressive state. Pharmacological inhibition of DNA methylation and histone modifications can augment the efficiency of immune checkpoint blockage, and unleash anti-tumour T-cell responses. However, these non-specific agents also represent a 'double-edged sword', as they can also reactivate gene transcription of checkpoint molecules, interrupting immune surveillance programmes. By understanding the impact of epigenetic control on the tumour microenvironment, rational combinatorial epigenetic and checkpoint blockage therapies have the potential to harness the immune system for the treatment of cancer.

Anticancer potential of naturally occurring immunoepigenetic modulators: A promising avenue?

“…. A large body of evidence suggests that epigenetic mechanisms commonly altered during tumorigenesis also participate in tumor immune escape mechanisms by affecting tumor‐associated immune cells to establish and maintain an immunosuppressive tumor microenvironment (TME) …”

“…It appears that early hypomethylation of CTA promoters during tumorigenesis is responsible for their specific expression in neoplastic cells; nevertheless, some CTAs also are frequently hypermethylated in certain cancers. Accordingly, the treatment of cancer cells with DNMT and HDAC inhibitors, either alone or in combination, consistently enhances or restores TAA expression, thus eliciting effective antitumor immunity . In addition to TAA expression, an efficient antitumor immune response requires the expression of antigen‐presenting machinery (APM)‐related genes and or major histocompatibility complex class I (MHCI)‐related and MHCII‐related genes.…”

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

“…A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma reported that bortezomib‐based treatment was associated with a low incidence of cardiac events . Epigenetic cancer therapy using histone deacetylase inhibitors is also emerging, as epigenetic gene silencing is a hallmark of cancer cells. Two important types of epigenetic changes are DNA methylation by DNA methyltransferases (DNMTs) and histone modification by histone deacetylases (HDACs) .…”

“…Epigenetic cancer therapy using histone deacetylase inhibitors is also emerging, as epigenetic gene silencing is a hallmark of cancer cells. Two important types of epigenetic changes are DNA methylation by DNA methyltransferases (DNMTs) and histone modification by histone deacetylases (HDACs) . DNMTs and HDACs have become attractive therapeutic targets, and several HDAC inhibitors e.g., Romidepsin, Belinostat, and Panobinostat, have been used in the clinic.…”

“…This resistance is because of alternative oncogenic pathways taking over and/or other mechanisms (e.g., bypass pathways), leading to the occurrence of drug‐resistant variants . Cancer cells may become drug resistant much more rapidly than would be predicted from the rates of conventional mutation by differential utilization of genomic and epigenetic strategies at various levels through point mutations, deletions, translocations, amplifications, altered microRNA levels, and epigenetic anomalies (epimutations) . Therefore, irreversible inhibitors may also need to be combined with other targeted agents and/or chemotherapy to address drug resistance .…”