Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

Abstract

Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.

Keywords: Antitumor immunity; DNA methylation; Epigenetic reprogramming; Heterogeneity; Histone modifications; Immune cells; Metabolic reprogramming; T cells.

Fig. 1

Overview of balanced states of transcription status maintained by the versatile chromatin proteins and histone posttranslational modifications, as well as DNA methylation in the promoter region. The histone-modifying enzymes can be divided into two classes for activation and repression. The chromatin states are maintained and balanced by a number of activation marks and repression marks. Histone marks highlighted in bold represent hallmarks of euchromatin (H4K16ac) and heterochromatin (H3K9me3 and H3K27me3), respectively. DNA methylation and histone modifications on the promoter region cross-talks [44], to dictate the transcriptional activity of the gene. The repressive marks may include H3K9me3, H3K27me3, H4K20me2/3, H2AK119ub, H3R2me, biotinylation, sumoylation and citrullination, while activation markers may include H3K4me1/2/3, H3K9me1, H3K27me1, H4k20me1, H3K36me1/2/3, H3K79me1/2/3, H3K27ac and butyrylation [45]

Fig. 2

The potential functions of epigenetic modulators in multiple aspects of the TME and immune cycle. First, epigenetic drugs may induce ICD of cancer cells, enhance the expression of various tumor-associated antigens (TAAs), MHC molecules, and the generation of APC, thus enhancing immune cell priming and effector T cell recognition of tumor target cells. DNMTi, HDACi and HMTi (EZH2 and G9a) have demonstrated such biological effects [–116]. Secondly, epigenetic drugs may target a variety of types of immune cells, resulting in reduced generation and accumulation of MDSC [117, 118], and inhibited differentiation and function of Treg (e.g., EZH2i) [–121]. Third, during these processes, the drugs commonly result in compensatory increases in the production of effector T cells-chemokines and the activation of effector (anti-tumor) T cells, with therapeutic synergy observed for combined use with immune checkpoint blockade agents. The detailed effects of various classes of inhibitors have been discussed under various Sections. This figure is modified from Chen X. et al., 2020 [122]