EPIGENETIC REGULATION OF ANTITUMOR IMMUNITY: NEW FRONTIERS IN CANCER IMMUNOTHERAPY

Abstract

While oncology has vastly changed with the arrival of cancer immunotherapy, the issue of resistance obstacles (primary and acquired) to durable responses is still omnipresent. Recently, epigenetic mechanisms such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs have come to play important roles in the regulation of tumor antigenicity, antigen presentation, interferon signaling, expression of immune checkpoints, and functional status of infiltrating immune cells. Both malignant cells and immune cells show epigenetic dysregulation that leads to immune evasion and formation of immunosuppressive tumor microenvironment, including T-cell exhaustion, macrophage polarization to M2 type and generation of myeloid-derived suppressor cells. Of note, epigenetic modifications can be reversed, which is not true for genetic changes, and therefore may provide a novel therapeutic opportunity. Epigenetic-targeting agents such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, EZH2 inhibitors and BET inhibitors can induce the re-expression of silenced tumor antigens and re-establish antigen presentation, alter immune checkpoints, and re-educate other (immunosuppressive) myeloid cells, transforming immunologically "cold" tumors into "hot" tumors that are responsive to immune checkpoint blockade. However, trials of epigenetic treatment in conjunction with immunotherapy have produced promising but inconsistent outcomes, and there are a number of obstacles to wide-scale use, such as varying efficacy on different types of disease context, off-target effects and the requirement for predictive biomarkers. The development of emerging single-cell and spatial epigenomic technologies, multi-omic integration, and precision epigenetic editing holds the promise of achieving cell, locus, and context specific interventions. In this review, the molecular mechanisms by which epigenetic modifications are connected to antitumor immune responses are summarized, existing therapeutic approaches and clinical findings are discussed, and the future path for precision epigenetic tumor immunotherapies that boost the success of the treatment while limiting its toxicity is outlined.