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.

Keywords: acetylation; cancer; histone methylation; immunotherapy.

Figure 1

Histone acetylation. Left panel: Acetylation of histones maintains the “relaxed” status of chromatin. Transcription factors (TF) can easily bind to the DNA, hence promoting gene expression Right panel: Deacetylation of histones induces the formation of tightly packed nucleosomes, which suppress the binding of transcription factors to DNA and hence inhibits gene expression.

Figure 2

Histone methylation. The methylation status of a histone is reversible. In contrast to histone acetylation, methylation of histones on different residues suppresses or enhances gene transcription. Methylation of H3K4 and H3K36 induces an open histone structure and hence promotes transcription. Methylation of H3K9 and H3K27 induces a compacted histone structure and hence suppresses gene transcription.

Figure 3

Histone modifications modulate the immune response. (1) HDACis are able to modulate the immune innate and adaptive immune host cells and other components of the immune system. HDACis enhance the expression of tumor-associated antigens (TAAs), co-stimulatory molecules, death receptors, and major histocompatibility complex (MHC) molecules on the surface of tumor cells. In natural killer (NK) cells, HDACis enhance the expression of NKG2D and the secretion of cytotoxic granules. In antigen-presenting cells (APCs), HDACis induce the expression of human leukocyte antigens (HLA) class I molecules. In cytotoxic T lymphocytes (CTLs), HDACis increase the expression of co-stimulatory molecules and the secretion of cytotoxic granules. HDACis also suppress the function and populations of myeloid-derived suppressor cells (MDSCs) and Tregs. (2) Histone methyltransferase inhibitors (HMTis) enhance the expression of NKG2D and promote NK cell activation. HMTis suppress the function of Tregs, enhance the secretion of chemokines, and promote infiltration of Teffs.