Enhancing the Anticancer Efficacy of Immunotherapy through Combination with Histone Modification Inhibitors

Abstract

In the nucleus of each cell, the DNA is wrapped around histone octamers, forming the so-called “nucleosomal core particles”. The histones undergo various modifications that influence chromatin structure and function, including methylation, acetylation, ubiquitination, phosphorylation, and SUMOylation. These modifications, known as epigenetic modifications (defined as heritable molecular determinants of phenotype that are independent of the DNA sequence), result in alterations of gene expression and changes in cell behavior. Recent work has shown that epigenetic drugs targeting histone deacetylation or methylation modulate the immune response and overcome acquired resistance to immunotherapy. A number of combination therapies involving immunotherapy and epigenetic drugs, which target histone deacetylation or methylation, are currently under various clinical/pre-clinical investigations and have shown promising anticancer efficacy. These combination therapies may provide a new strategy for achieving sustained anticancer efficacy and overcoming resistance.

Role of Methylation in Pro- and Anti-Cancer Immunity

“…Epigenetic mechanisms including miRNAs and histone modifications are crucial for the regulation of the immune system in the TME and has been extensively reviewed [ 45 , 46 , 47 , 48 , 49 ]. DNA methylation also plays an essential role in the differentiation and function of immune cells into various subtypes, and the manner in which these immune cells influence each other in the TME, which ultimately results in tumor progression or suppression.…”

Post translational modification-assisted cancer immunotherapy for effective breast cancer treatment

“…38 These antigens can promote an inammatory immune response as well as affect the immunogenicity of cancer cells. 39 Anoctamin is another type of tumor antigen over expressed in breast cancer and related to poor prognosis of patients. 40,41 To highlight the advantage of surface modication in specic binding, the total amount of proteins and the number of self-proteins enriched by each nanoparticle formulation were also quantied ( Fig.…”

Novel Approaches to Epigenetic Therapies: From Drug Combinations to Epigenetic Editing

“…Accumulating evidence shows that combining epigenetic drugs targeting histone deacetylation or methylation with immunotherapeutics is beneficial. It has been shown that DNMTi and HDACi modulate the immune response and overcome acquired resistance to immunotherapy [ 69 ]. The mechanisms by which such combined therapies exert their actions are still awaiting elucidation, but it is suggested that the reactivation of tumor-surface antigens, endogenous retroviruses, and proteins for the major complex of histocompatibility could be mediators of the increased tumor visibility to the host immune system [ 3 , 70 ].…”