دورية أكاديمية
أعرض في EDS

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches.

التفاصيل البيبلوغرافية
العنوان: Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches.
المؤلفون: Lofiego MF; University of Siena, Siena, Italy., Piazzini F; University of Siena, Siena, Italy., Caruso FP; BIOGEM Institute of Molecular Biology and Genetics, Ariano Irpino, Italy.; Department of Electrical Engineering and Information Technology (DIETI), University of Naples 'Federico II', Naples, Italy., Marzani F; University of Siena, Siena, Italy., Solmonese L; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy., Bello E; University of Siena, Siena, Italy., Celesti F; University of Siena, Siena, Italy., Costa MC; BIOGEM Institute of Molecular Biology and Genetics, Ariano Irpino, Italy.; Department of Electrical Engineering and Information Technology (DIETI), University of Naples 'Federico II', Naples, Italy., Noviello T; BIOGEM Institute of Molecular Biology and Genetics, Ariano Irpino, Italy.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.; Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA., Mortarini R; Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Anichini A; Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Ceccarelli M; BIOGEM Institute of Molecular Biology and Genetics, Ariano Irpino, Italy.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.; Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA., Coral S; University of Siena, Siena, Italy., Di Giacomo AM; University of Siena, Siena, Italy.; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy., Maio M; University of Siena, Siena, Italy.; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy., Covre A; University of Siena, Siena, Italy. alessia.covre2@unisi.it.
مؤلفون مشاركون: EPigenetic Immune-oncology Consortium Airc (EPICA) investigators
المصدر: Journal of translational medicine [J Transl Med] 2024 Mar 01; Vol. 22 (1), pp. 223. Date of Electronic Publication: 2024 Mar 01.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : BioMed Central, 2003-
مواضيع طبية MeSH: Glioblastoma*/genetics , Glioblastoma*/therapy , Glioblastoma*/metabolism, Azacitidine/*analogs & derivatives, Humans ; Azacitidine/therapeutic use ; Epigenesis, Genetic ; Immunotherapy
مستخلص: Background: Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor, that is refractory to standard treatment and to immunotherapy with immune-checkpoint inhibitors (ICI). Noteworthy, melanoma brain metastases (MM-BM), that share the same niche as GBM, frequently respond to current ICI therapies. Epigenetic modifications regulate GBM cellular proliferation, invasion, and prognosis and may negatively regulate the cross-talk between malignant cells and immune cells in the tumor milieu, likely contributing to limit the efficacy of ICI therapy of GBM. Thus, manipulating the tumor epigenome can be considered a therapeutic opportunity in GBM.
Methods: Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were performed to study the differences in the constitutive expression profiles of GBM vs MM-BM cells, compared to the extracranial MM cells and to investigate the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine among the different tumor cells. The prognostic relevance of DHA-modulated genes was tested by Cox analysis in a TCGA GBM patients' cohort.
Results: The most striking differences between GBM and MM-BM cells were found to be the enrichment of biological processes associated with tumor growth, invasion, and extravasation with the inhibition of MHC class II antigen processing/presentation in GBM cells. Treatment with guadecitabine reduced these biological differences, shaping GBM cells towards a more immunogenic phenotype. Indeed, in GBM cells, promoter hypomethylation by guadecitabine led to the up-regulation of genes mainly associated with activation, proliferation, and migration of T and B cells and with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% showed a significant prognostic relevance. Moreover, a large set of immune-related upstream-regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and MM cells: DHA-activated URs enriched for biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and in Type I/II/III IFN-mediated signaling; conversely, DHA-inhibited URs were involved in metabolic and proliferative pathways.
Conclusions: Epigenetic remodeling by guadecitabine represents a promising strategy to increase the efficacy of cancer immunotherapy of GBM, supporting the rationale to develop new epigenetic-based immunotherapeutic approaches for the treatment of this still highly deadly disease.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 5 per Mille 2018 - ID.21073 Associazione Italiana per la Ricerca sul Cancro
فهرسة مساهمة: Keywords: Brain metastases; DNA hypomethylating agent; Glioblastoma; Immunotherapy; Melanoma
المشرفين على المادة: 2KT4YN1DP7 (guadecitabine)
M801H13NRU (Azacitidine)
تواريخ الأحداث: Date Created: 20240301 Date Completed: 20240304 Latest Revision: 20240711
رمز التحديث: 20240711
مُعرف محوري في PubMed: PMC10908027
DOI: 10.1186/s12967-024-05040-x
PMID: 38429759
قاعدة البيانات: MEDLINE
الوصف
تدمد:1479-5876
DOI:10.1186/s12967-024-05040-x