Landscape of immune-related signatures induced by targeting of different epigenetic regulators in melanoma: implications for immunotherapy.

Autor: Anichini A; Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy. andrea.anichini@istitutotumori.mi.it., Molla A; Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy., Nicolini G; Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy., Perotti VE; Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy., Sgambelluri F; Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy., Covre A; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy.; University of Siena, Siena, Italy., Fazio C; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy., Lofiego MF; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy., Di Giacomo AM; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy.; University of Siena, Siena, Italy., Coral S; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy., Manca A; Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy., Sini MC; Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy., Pisano M; Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy., Noviello T; Department of Electrical Engineering and Information Technology (DIETI), University of Naples 'Federico II', Naples, Italy.; BIOGEM Institute of Molecular Biology and Genetics, Ariano Irpino, Italy., Caruso F; Department of Electrical Engineering and Information Technology (DIETI), University of Naples 'Federico II', Naples, Italy.; BIOGEM Institute of Molecular Biology and Genetics, Ariano Irpino, Italy., Brich S; Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Pruneri G; Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.; University of Milan, School of Medicine, Milan, Italy., Maurichi A; Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Santinami M; Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Ceccarelli M; Department of Electrical Engineering and Information Technology (DIETI), University of Naples 'Federico II', Naples, Italy.; BIOGEM Institute of Molecular Biology and Genetics, Ariano Irpino, Italy., Palmieri G; Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy.; University of Sassari, Sassari, Italy., Maio M; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy.; University of Siena, Siena, Italy., Mortarini R; Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2022 Nov 17; Vol. 41 (1), pp. 325. Date of Electronic Publication: 2022 Nov 17.
DOI: 10.1186/s13046-022-02529-5
Abstrakt: Background: Improvement 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.
Methods: Melanoma 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.
Results: Epigenetic 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.
Conclusions: The 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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