Table 1.
The crosstalk between DNA methylation/histone modification and melanoma immunology.
| Class of epigenetic alteration | Aspect of melanoma immunology | Detailed underlying mechanism | References |
|---|---|---|---|
| DNA methylation | Tumor cell immunologic characteristics | Promoter hypermethylation of the HLA class I and II molecules leads to downregulation of HLA antigens | (63–66) |
| Promoter hypermethylation suppresses endogenous retrovirus (ERV) genes, the cytosolic sensing of double-stranded RNA (dsRNA), and the downstream type I interferon response | (67) | ||
| Promoter hypermethylation of cGAS-STING genes induces widespread impairment of the STING signaling | (18) | ||
| TET2 deficiency significantly reduces chemokine expression and TILs, enabling tumors to evade antitumor immunity and to resist anti-PD-L1 immunotherapy | (69) | ||
| Promoter hypermethylation of PD-L1, PD-L2, CTLA-4, LAG3, TIM-3, and Galectin-9 induces their downregulation | (70–76) | ||
| Antitumor capacity of immune cells | Methylation pattern resembles stromal and leukocyte cells, and an overexpressed immune signature | (77) | |
| Gp96 engages conventional and plasmacytoid dendritic cells (pDCs) by altering global methylation via CD91 | (78) | ||
| DNA hypomethylating agent promotes CD8+ T-cell infiltration and cytotoxic function | (79) | ||
| Histone modification | Tumor cell immunologic characteristics | Histone deacetylase inhibitors promote the expressions TAP1, TAP2, LMP2, LMP7, and Tapasin and facilitate antigen processing and presentation. | (80, 81) |
| HDAC inhibitor induces prominent upregulation of PD-L1, increasing the efficacy of anti-PD-1 antibody | (20) | ||
| LSD1 ablation increases tumor immunogenicity by upregulating ERV transcripts and suppressing RNA-induced silencing complex | (82) | ||
| Histone methylase EZH2 induces the suppression of IFN-γ signature | (83) | ||
| Antitumor capacity of immune cells | Histone deacetylase SIRT1 impedes the differentiation of Th17 cells via the reduction of STAT3 acetylation | (84) | |
| HDAC6 inhibition results in downregulation of Th2 transcription factor GATA3, upregulation of the Th1 transcription factor T-Bet, accumulation of central memory phenotype T cells, reduced exhaustion-associated phenotypes, and enhanced killing in mixed lymphocyte reactions | (85) | ||
| SIRT2 overexpression suppresses the infiltration and function of natural killer cells in tumor microenvironment | (86) | ||
| Targeting LSD1 phosphorylation effectively induces IFN-γ/TNF-α-expressing CD8+ T-cell infiltration into the tumors | (87) | ||
| EZH2-mediated histone H3 methylation of HIF1α in macrophages reprograms the immune suppressive microenvironment to the facilitative one | (88) |