A New Trend in Cancer Treatment: The Combination of Epigenetics and Immunotherapy

Abstract

In recent years, immunotherapy has become a hot spot in the treatment of tumors. As an emerging treatment, it solves many problems in traditional cancer treatment and has now become the main method for cancer treatment. Although immunotherapy is promising, most patients do not respond to treatment or develop resistance. Therefore, in order to achieve a better therapeutic effect, combination therapy has emerged. The combination of immune checkpoint inhibition and epigenetic therapy is one such strategy. In this review, we summarize the current understanding of the key mechanisms of how epigenetic mechanisms affect cancer immune responses and reveal the key role of epigenetic processes in regulating immune cell function and mediating anti-tumor immunity. In addition, we highlight the outlook of combined epigenetic and immune regimens, particularly the combination of immune checkpoint blockade with epigenetic agents, to address the limitations of immunotherapy alone.

Keywords: T cells; cancer therapy; epigenetic regulation; epigenetics; immune checkpoint therapy; immunotherapy.

Figure 1

DNA demethylation restores ERV expression to induce viral mimicry. DNA demethylating drugs reactivate ERV promoters by inhibiting their methylation, resulting in bidirectional transcription of ERVs to produce dsRNAs, which are exported to the cytoplasm and sensed by pattern recognition receptors, such as MDA5. MDA5 binding to dsRNA induces recruitment of TANK-binding kinase 1 (TBK1) and aggregation of mitochondrial antiviral signaling protein (MAVs), which activate interferon regulatory factor 7(IRF7) by phosphorylation. Then, activated IRF7 moves into the nucleus and induces transcription of interferon-responsive genes (IRG). Consequently, type I/III interferons are produced, transported, and secreted into the tumor microenvironment. Secreted type I/III interferons increase the expression of antigen processing and antigen presentation mechanisms, improving the ability of cancer cells to present antigens.

Figure 2

Combining epigenetic drugs with immune checkpoint inhibitors. Persistent antigen stimulation and inflammatory factors in chronic inflammation can cause dysfunction of tumor-infiltrating T cells, up-regulation of immune checkpoints, and production of immune evasion, which are associated with epigenetic modifications. Anti-PD-1 relieves the inhibitory effect of the epidemic checkpoint on tumor cells and antigen presenting cells by blocking the binding of PD-1 to its ligands PD-L1 and PD-L2 in the tumor microenvironment. Epigenetic modifiers can enhance antigen presentation by tumor cells, thereby enhancing the immune effects of T cells. Moreover, epigenetic modifiers inhibitors, such as BET, can also inhibit the expression of PD-L1 on the surface of tumor cells and tumor-infiltrating immune cells. Moreover, EZH2 inhibitors prevent the conversion of CD4 T cells into Treg cells to up-regulate the immune response of other cells. Therefore, the combination therapy of epigenetic modifiers with immune checkpoint inhibitors embodies great advantages.