Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma III
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PROVIDER: PRJNA783918 | ENA |
REPOSITORIES: ENA
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Project description: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. This experiment deals with the characterization of gene expression in tumor nodules removed from immunodeficient mice treated or not with guadecitabine (as described in Covre A et al. Seminars in Oncology 2015;42:506-513) after s.c. tranplant of human melanoma cells from two cell lines 313 and 195 (cell lines described in Coral S et al. J. Cell Physiol 2006;207:58-66).
2022-11-23 | GSE189630 | GEO
Project description:Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma II
| PRJNA783919 | ENA
Project description:Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma IV
| PRJNA783917 | ENA
Project description:Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma I
| PRJNA783920 | ENA
Project description: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. This experiment deals with the characterization of gene expression in untreated human melanoma cell lines used throughout the project.
2022-11-23 | GSE189628 | GEO
Project description: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. This experiment deals with the characterization of gene modulation by epigenetic drugs (guadecitabine, givinostat, JQ1, GSK-126) and by the unrelated drug Abemaciclib in two melanoma cells lines CST30 and VRG100
2022-11-23 | GSE189629 | GEO
Project description: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.
2022-11-23 | GSE189631 | GEO
Project description:BackgroundImprovement of efficacy of immune checkpoint blockade (ICB) remains a major clinical goal. Association of ICB with immunomodulatory epigenetic drugs is an option. However, epigenetic inhibitors show a heterogeneous landscape of activities. Analysis of transcriptional programs induced in neoplastic cells by distinct classes of epigenetic drugs may foster identification of the most promising agents.MethodsMelanoma cell lines, characterized for mutational and differentiation profile, were treated with inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), BET proteins (JQ1 and OTX-015), and enhancer of zeste homolog 2 (GSK126). Modulatory effects of epigenetic drugs were evaluated at the gene and protein levels. Master molecules explaining changes in gene expression were identified by Upstream Regulator (UR) analysis. Gene set enrichment and IPA were used respectively to test modulation of guadecitabine-specific gene and UR signatures in baseline and on-treatment tumor biopsies from melanoma patients in the Phase Ib NIBIT-M4 Guadecitabine + Ipilimumab Trial. Prognostic significance of drug-specific immune-related genes was tested with Timer 2.0 in TCGA tumor datasets.ResultsEpigenetic drugs induced different profiles of gene expression in melanoma cell lines. Immune-related genes were frequently upregulated by guadecitabine, irrespective of the mutational and differentiation profiles of the melanoma cell lines, to a lesser extent by givinostat, but mostly downregulated by JQ1 and OTX-015. GSK126 was the least active drug. Quantitative western blot analysis confirmed drug-specific modulatory profiles. Most of the guadecitabine-specific signature genes were upregulated in on-treatment NIBIT-M4 tumor biopsies, but not in on-treatment lesions of patients treated only with ipilimumab. A guadecitabine-specific UR signature, containing activated molecules of the TLR, NF-kB, and IFN innate immunity pathways, was induced in drug-treated melanoma, mesothelioma and hepatocarcinoma cell lines and in a human melanoma xenograft model. Activation of guadecitabine-specific UR signature molecules in on-treatment tumor biopsies discriminated responding from non-responding NIBIT-M4 patients. Sixty-five % of the immune-related genes upregulated by guadecitabine were prognostically significant and conferred a reduced risk in the TCGA cutaneous melanoma dataset.ConclusionsThe DNMT inhibitor guadecitabine emerged as the most promising immunomodulatory agent among those tested, supporting the rationale for usage of this class of epigenetic drugs in combinatorial immunotherapy approaches.
| S-EPMC9670381 | biostudies-literature
Project description:Prediction of outcome for melanoma patients with surgically-resected macroscopic nodal metastases is very imprecise. We performed a comprehensive clinicopathologic assessment of fresh-frozen macroscopic nodal metastases and the preceding primary melanoma, somatic mutation profiling and gene expression profiling to identify determinants of outcome in 79 melanoma patients. In addition to disease stage <II at initial presentation, the following clinical and pathologic factors were independent predictors of improved outcome (ORs for survival >4yr, 90%CI): presence of a nodular component in the primary melanoma (6.8, 0.6-76.0), and small cell size (11.1, 0.8-100.0) or low pigmentation (3.0, 0.8-100.0) in the nodal metastases. Absence of BRAF mutation (20.0, 1.0-1000.0) or NRAS mutation (16.7, 0.6-1000.0) were both favourable prognostic factors. A 46-gene expression signature with strong over-representation of immune response genes was predictive of better survival (10.9, 0.4-325.6); in the full cohort median survival was >100 months in those with the signature, but 10 months in those without. This relationship was validated in two previously published independent stage III melanoma datasets. We conclude that the presence of BRAF mutation, NRAS mutation and absence of an immune-related expressed gene profile predict poor outcome in melanoma patients with macroscopic stage III disease.
2013-12-10 | GSE53118 | GEO
Project description:Steatohepatitis-induced vascular niche alterations promote melanoma metastasis III
| PRJNA1101953 | ENA