Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma IV

Epigenetic drugs exert a wide range of immune-related effects, but have strong drug-specific heterogeneity in immunomodulation, thus hampering selection of the most promising agent for innovative cancer immunotherapy approaches. Here we identified immune-related signatures induced by four classes of epigenetic drugs in melanoma cells to define the most active agent and to understand its biological activity in -vitro, in a pre-clinical model and in clinical samples. Gene modulation, induced by inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), bromodomain and extraterminal domain proteins (JQ1 and OTX-015) and enhancer of zeste homolog 2 (GSK126), was assessed in human melanoma cell lines. All drugs modulated genes belonging to 20 families. Guadecitabine, followed by givinostat, was the most active drug and upregulated >160 immune-related genes characterized by low expression and high methylation. JQ1 and OTX-015 showed predominant inhibitory effects, GSK126 was the least active. A dominant immunomodulatory effect of guadecitabine and JQ1 was observed in combinatorial treatments. Gene modulation in melanoma cell lines treated with epigenetic drugs was assessed by NanoString nCounter PanCancer Immune profiling panel. The following cell lines were evaluated for immune-related gene modulation by Guadecitabine, Decitabine, Givinostat, JQ1, GSK126 and an unrelated drug abemaciclib: VRG100, BRM17, FRN39, CST30, BNV13, MNT59, GRD43, GML41, CPN20, SLN91. The following six cell lines were treated also with OTX-015: BRM17, VRG100, GRD43, FRN39, CPN20 and SLN91. The following six cell lines were also treated with combinations of the epigenetic drugs: GRD43, BNV13, FRN39, CPN20, SLN91 and MNT59. Overall the experiment includes 107 arrays.