Epigenetics Regulates Antitumor Immunity in Melanoma

Abstract

Melanoma is the most malignant skin cancer, which originates from epidermal melanocytes, with increasing worldwide incidence. The escape of immune surveillance is a hallmark of the tumor, which is manifested by the imbalance between the enhanced immune evasion of tumor cells and the impaired antitumor capacity of infiltrating immune cells. According to this notion, the invigoration of the exhausted immune cells by immune checkpoint blockades has gained encouraging outcomes in eliminating tumor cells and significantly prolonged the survival of patients, particularly in melanoma. Epigenetics is a pivotal non-genomic modulatory paradigm referring to heritable changes in gene expression without altering genome sequence, including DNA methylation, histone modification, non-coding RNAs, and m6A RNA methylation. Accumulating evidence has demonstrated how the dysregulation of epigenetics regulates multiple biological behaviors of tumor cells and contributes to carcinogenesis and tumor progression in melanoma. Nevertheless, the linkage between epigenetics and antitumor immunity, as well as its implication in melanoma immunotherapy, remains elusive. In this review, we first introduce the epidemiology, clinical characteristics, and therapeutic innovations of melanoma. Then, the tumor microenvironment and the functions of different types of infiltrating immune cells are discussed, with an emphasis on their involvement in antitumor immunity in melanoma. Subsequently, we systemically summarize the linkage between epigenetics and antitumor immunity in melanoma, from the perspective of distinct paradigms of epigenetics. Ultimately, the progression of the clinical trials regarding epigenetics-based melanoma immunotherapy is introduced.

LINC01296 promotes proliferation of cutaneous malignant melanoma by regulating miR-324-3p/MAPK1 axis

“…The patients with CMM are often diagnosed as advanced stage due to the inadequate attention, which is explained as one of the reasons for its poor prognosis and high mortality [ 19 ]. So due to the unsatisfaction of relatively poor diagnosis and prognosis of CMM, numerous studies on association between the related factors and the treatment of CMM have been receiving increasing attention [ 20 , 21 ]. Therefore, searching for these novel treatments are of great significance for CMM.…”

“…Therefore, searching for these novel treatments are of great significance for CMM. There is growing evidence that lncRNAs play a broad regulatory role as active biomolecules in the carcinogenesis and progression of CMM [ 14 , 15 , 20 ]. Depending on the location, lncRNAs can achieve their functions by being implicated in the production and progression of target genes on various levels [ 14 , 16 ].…”

Exploring the role of epigenetic alterations and non-coding RNAs in melanoma pathogenesis and therapeutic strategies

“…Serrano et al demonstrated that hypermethylation of HLA-A and HLA-B genes in tumor cells can switch off HLA class genes and enable melanoma cells to escape immune surveillance and recognition. Treatment with a demethylating agent 5'-aza-2'-deoxycytidine (DAC) allows HLA-A and HLA-B transcription can restore tumor cell recognition by cytotoxic T lymphocytes (CTL) [58][59][60][61].…”

“…Encouragingly, this combinatorial approach proved safe and well-tolerated, demonstrating favorable immunomodulatory and antitumor activity [75]. Equally noteworthy are ongoing trials investigating the synergy between epigenetic agents and immunotherapy in the context of melanoma [59]. In the vein of HDAC6, its role in regulating PD-L1 expression in melanoma by activating STAT3, thereby impacting the growth and progression of melanoma, has been underscored.…”

Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells

“…On the other hand, there is increasing evidence that melanoma pathogenesis is also associated with specific aberrant epigenetic modifications, leading to drug-acquired resistance, evasion of the immune system, apoptosis, and increased metastatic potential. Thus, the reversal of an abnormal epigenetic landscape appears to be a promising therapeutic approach, such as in the case of EZH2 (Enhancer of Zeste Homologue 2; a histone methyltransferase) over-expression and its role in melanoma development and progression [ 5 , 6 , 7 , 8 , 9 ].…”