**Author details**

The most promising immunotherapies currently in clinical use are anti-PD-1 and PD-L1 therapies [98]. Analyses of 52 immunotherapy-naïve stage III melanomas specimens in regard to the PD-L1 expression suggested that PD-L1 negative status is associated with worse prognosis and a poor immune response gene signature. PD-L1 positive melanomas showed a significant association with the TCGA hypomethylation cluster suggesting that upregulation of immune checkpoint inhibitors is found in cancer cells with altered gene expression. Another study showed that treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine activates a viral defense pathway. Expression levels of these viral defense genes grouped different cancers including melanoma into separate categories where high expression was associated with the TCGA immune reactive (IMR) tumors with a good prognosis [99]. Melanoma patients with high levels of the viral defense signature correlated with response to anti-CTLA-4 for more than 6 month and combined treatment of 5-aza-2′-deoxycytidine and anti-CTLA4 immune checkpoint therapy in a B16-F10 mouse melanoma model enhanced tumor responses [99]. Another important factor for the successful immunotherapy response is the expression of tumor-associated antigens [100]. Along this line, it has been shown that the expression of high molecular weight-melanoma associated antigen (HMW-MAA) is regulated by DNA methylation as its expression correlates with promoter methylation. As such it is

Multiple studies reported the importance of histone modifications for the regulation of immunogenic factors. For example, H3K4me3 dependent PD-L1 expression has been observed in pancreatic cancer [102] or H3K27me3 and DNA methylation-mediated silencing of Th1-type chemokines CXCL9 and CXCL10 in ovarian cancer cells [103], suggesting an important role for histone modifications in the regulation of immunomodulatory factors across different cancer types. Further evidence of epigenetically regulated PD-L1 expression is provided by studies using HDAC inhibitors in melanoma cell lines. Specifically, treatment with class I HDAC inhibitors resulted in increased acetylation of histone 3 in PD-L1 and PD-L2 promoter regions,

Keeping in mind the wealth of data describing epigenetic alterations during melanoma development and also in relation to the therapeutic response targeting or co-targeting these epigenetic events appears to be a very promising strategy for improving melanoma management. This is especially true in light of the highly heterogeneous and adaptive nature of melanoma which cannot be explained only by stable genetic events. While epigenetic biomarkers have not yet been put to clinical use, there is an overwhelming number of clinical trials utilizing and testing epigenetic drugs in different cancer types. These trials investigate the use of general epigenetic inhibitors targeting histone deacetylases, bromodomain and extra-terminal (BET) proteins (histone acetylation binding proteins) and more specific inhibitors targeting DNMT1, IDH1 and IDH2 (affect TET enzyme function), EZH2, DOT1L (histone H3K79 meth-

induced by treatment with 5-aza-2′-deoxycytidine [101].

16 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

**5. Conclusion**

yltransferase) or KDM1A [105].

which resulted in increased PD-L1 expression *in vitro* and *in vivo* [104].

Heinz Hammerlindl and Helmut Schaider\*

\*Address all correspondence to: h.schaider@uq.edu.au

Dermatology Research Centre, The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia
