DNA methylation in melanoma immunotherapy: mechanisms and therapeutic opportunities

Abstract

Abnormal DNA methylation is a hallmark of cancer and a nearly universal feature of melanoma. DNA methylation plays well-appreciated melanoma cell-intrinsic roles, including silencing tumor-suppressor genes, regulating genomic stability, deregulating expression of oncogenes to potentiate proliferative signaling and tumor migration. With the recent success of immunological therapies for melanoma, important roles for DNA methylation are also emerging at the interface between melanoma and immune cells with the potential to regulate the anti-tumor immune response. These newly recognized roles for DNA methylation in controlling melanoma cell immunogenicity, expression of MHC and immune checkpoint molecules as well as T cell phenotypes in the tumor microenvironment raise the possibility of using DNA methylation to develop improved therapies and methylation-based biomarkers. In addition to reviewing the "immune dimension" of DNA methylation, we summarize recent developments with potential clinical applications in melanoma, such as targeted DNA methylation editing, single-cell methylation approaches, and measurement of circulating methylated DNA. An improved understanding of the immune roles of DNA methylation presents an exciting opportunity for continued improvement of care and outcomes for patients with melanoma.

Fig. 1

Mechanisms by which hypomethylating agents may modulate tumor cells (left) and T cells (right) in the anti-tumor immune response. The hypomethylating agent, decitabine, has activity in tumor cells and T cells in increasing immunogenicity [35, 63]. DAC treatment induces ERV expression in tumor cells, activating the MDA-5/MAVS innate immune sensing pathway, resulting in type I interferon expression [35]. Type I interferons stimulate interferon-stimulated gene (ISG) expression. ERV expression induces the production of aberrant ERV-derived peptides, which are predicted to bind to class I MHC molecules recognized by T cell receptors on CTLs. DAC treatment also impacts anti-tumor CTLs by inducing preferential expression of short isoforms of NFATc1, associated with increased CTL effector function, cytotoxicity and increased survival [63]