Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma IV. 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. Overall design: 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.