Cancer Epigenetics, Tumor Immunity, and Immunotherapy

Abstract

Epigenetic mechanisms, including DNA methylation, histone post-translational modifications, and chromatin structure regulation, are critical for the interactions between tumor and immune cells. Emerging evidence shows that tumors commonly hijack various epigenetic mechanisms to escape immune restriction. As a result, the pharmaceutical modulation of epigenetic regulators, including 'writers', 'readers', 'erasers', and 'remodelers', is able to normalize the impaired immunosurveillance and/or trigger antitumor immune responses. Thus, epigenetic targeting agents are attractive immunomodulatory drugs and will have major impacts on immuno-oncology. Here, we discuss epigenetic regulators of the cancer-immunity cycle and current advances in developing epigenetic therapies to boost anticancer immune responses, either alone or in combination with current immunotherapies.

Keywords: antitumor immune responses; cancer epigenetics; cancer–immunity cycle; epigenetic drugs; immuno-oncology; immunotherapy.

Figure 1.. Molecular Basis of Chromatin-Based Epigenetic Mechanisms and their Regulators.

Genomic DNA is wrapped around histone octamers to form nucleosomes, which are further packaged into the human nucleus in a highly organized manner. The packaging states of chromatin are dynamically regulated by chromatin-remodeling complexes (‘remodelers’) to allow or deny access of selected cis-elements by their trans-factors. Core histones can be modified at multiple residues through covalent bonds by methylation, acetylation, phosphorylation, ubiquitination, and many other modifications. DNA can be methylated (or hydroxymethylated) at the 5th position on the pyrimidine ring in cytosines, and less commonly in mammals at the nitrogen in the 6th position on the adenine in adenosines. Histone post-translational modifications and DNA methylation are added or removed by specific enzymes (‘writers’ and ‘erasers’, respectively) and recognized by their binding proteins (‘readers’).

Figure 2.. The Cancer–Immunity Cycle.

The cancer–immunity cycle comprises six major steps: (1) releasing: tumor-associated antigens are released by tumor cells into the microenvironment, mostly due to cell death; (2) presenting: released antigens are captured by dendritic cells (DCs) in the tumor microenvironment (TME). Antigen-loaded DCs then process and present the antigens on the cell surface with major histocompatibility complex (MHC) complexes and travel to lymphoid organs; (3) priming: naïve T cells in lymphoid organs recognize selected peptide–MHC complexes through T cell receptors (TCRs), which triggers the priming and activation of effector T cells; (4) trafficking: differentiated effector T cells leave lymphoid organs, and travel along blood vessels to scan peripheral tissues until they find their antigens in tumors; (5) infiltrating: T cells enter the tumor bed and migrate into the TME to become tumor-infiltrating lymphocytes (TILs); and (6) attacking: T cells recognize cancer cells carrying the matched antigen through interaction between the TCR and peptide–MHC complex and kill cancer cells by direct or indirect immune attack. Immune attack leads to the release of additional antigens from the dying tumor cells, which triggers a new round of antitumor immune response.

Figure 3.. Major Epigenetic Regulation in Tumor Immunity.

Histone post-translational modifications and DNA methylation play key roles in adaptive immune response, including dendritic cell development and T cell priming and activation. In tumor cells, histone and DNA modifications affects production of tumor antigens, silencing of anti-tumor cytokines, and induction of the PD-L1 checkpoint. Recent studies revealed the contributions of chromatin remodeling responding to cytotoxic attack in tumor cells and exhaustion phenotype in tumor infiltrating CD8 T cells. Abbreviation: PD-L1, programmed death ligand 1.