Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches
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 I...
Ausführliche Beschreibung
Autor*in: |
Lofiego, Maria Fortunata [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2024 |
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Anmerkung: |
© The Author(s) 2024 |
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Übergeordnetes Werk: |
Enthalten in: Journal of translational medicine - London : BioMed Central, 2003, 22(2024), 1 vom: 01. März |
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Übergeordnetes Werk: |
volume:22 ; year:2024 ; number:1 ; day:01 ; month:03 |
Links: |
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DOI / URN: |
10.1186/s12967-024-05040-x |
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Katalog-ID: |
SPR054983819 |
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520 | |a 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. | ||
650 | 4 | |a Glioblastoma |7 (dpeaa)DE-He213 | |
650 | 4 | |a Brain metastases |7 (dpeaa)DE-He213 | |
650 | 4 | |a Immunotherapy |7 (dpeaa)DE-He213 | |
650 | 4 | |a DNA hypomethylating agent |7 (dpeaa)DE-He213 | |
650 | 4 | |a Melanoma |7 (dpeaa)DE-He213 | |
700 | 1 | |a Piazzini, Francesca |4 aut | |
700 | 1 | |a Caruso, Francesca Pia |4 aut | |
700 | 1 | |a Marzani, Francesco |4 aut | |
700 | 1 | |a Solmonese, Laura |4 aut | |
700 | 1 | |a Bello, Emma |4 aut | |
700 | 1 | |a Celesti, Fabrizio |4 aut | |
700 | 1 | |a Costa, Maria Claudia |4 aut | |
700 | 1 | |a Noviello, Teresa |4 aut | |
700 | 1 | |a Mortarini, Roberta |4 aut | |
700 | 1 | |a Anichini, Andrea |4 aut | |
700 | 1 | |a Ceccarelli, Michele |4 aut | |
700 | 1 | |a Coral, Sandra |4 aut | |
700 | 1 | |a Di Giacomo, Anna Maria |4 aut | |
700 | 1 | |a Maio, Michele |4 aut | |
700 | 1 | |a Covre, Alessia |0 (orcid)0000-0001-8721-5693 |4 aut | |
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10.1186/s12967-024-05040-x doi (DE-627)SPR054983819 (SPR)s12967-024-05040-x-e DE-627 ger DE-627 rakwb eng Lofiego, Maria Fortunata verfasserin aut Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Glioblastoma (dpeaa)DE-He213 Brain metastases (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA hypomethylating agent (dpeaa)DE-He213 Melanoma (dpeaa)DE-He213 Piazzini, Francesca aut Caruso, Francesca Pia aut Marzani, Francesco aut Solmonese, Laura aut Bello, Emma aut Celesti, Fabrizio aut Costa, Maria Claudia aut Noviello, Teresa aut Mortarini, Roberta aut Anichini, Andrea aut Ceccarelli, Michele aut Coral, Sandra aut Di Giacomo, Anna Maria aut Maio, Michele aut Covre, Alessia (orcid)0000-0001-8721-5693 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 22(2024), 1 vom: 01. März (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:22 year:2024 number:1 day:01 month:03 https://dx.doi.org/10.1186/s12967-024-05040-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 01 03 |
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10.1186/s12967-024-05040-x doi (DE-627)SPR054983819 (SPR)s12967-024-05040-x-e DE-627 ger DE-627 rakwb eng Lofiego, Maria Fortunata verfasserin aut Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Glioblastoma (dpeaa)DE-He213 Brain metastases (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA hypomethylating agent (dpeaa)DE-He213 Melanoma (dpeaa)DE-He213 Piazzini, Francesca aut Caruso, Francesca Pia aut Marzani, Francesco aut Solmonese, Laura aut Bello, Emma aut Celesti, Fabrizio aut Costa, Maria Claudia aut Noviello, Teresa aut Mortarini, Roberta aut Anichini, Andrea aut Ceccarelli, Michele aut Coral, Sandra aut Di Giacomo, Anna Maria aut Maio, Michele aut Covre, Alessia (orcid)0000-0001-8721-5693 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 22(2024), 1 vom: 01. März (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:22 year:2024 number:1 day:01 month:03 https://dx.doi.org/10.1186/s12967-024-05040-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 01 03 |
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10.1186/s12967-024-05040-x doi (DE-627)SPR054983819 (SPR)s12967-024-05040-x-e DE-627 ger DE-627 rakwb eng Lofiego, Maria Fortunata verfasserin aut Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Glioblastoma (dpeaa)DE-He213 Brain metastases (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA hypomethylating agent (dpeaa)DE-He213 Melanoma (dpeaa)DE-He213 Piazzini, Francesca aut Caruso, Francesca Pia aut Marzani, Francesco aut Solmonese, Laura aut Bello, Emma aut Celesti, Fabrizio aut Costa, Maria Claudia aut Noviello, Teresa aut Mortarini, Roberta aut Anichini, Andrea aut Ceccarelli, Michele aut Coral, Sandra aut Di Giacomo, Anna Maria aut Maio, Michele aut Covre, Alessia (orcid)0000-0001-8721-5693 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 22(2024), 1 vom: 01. März (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:22 year:2024 number:1 day:01 month:03 https://dx.doi.org/10.1186/s12967-024-05040-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 01 03 |
allfieldsGer |
10.1186/s12967-024-05040-x doi (DE-627)SPR054983819 (SPR)s12967-024-05040-x-e DE-627 ger DE-627 rakwb eng Lofiego, Maria Fortunata verfasserin aut Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Glioblastoma (dpeaa)DE-He213 Brain metastases (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA hypomethylating agent (dpeaa)DE-He213 Melanoma (dpeaa)DE-He213 Piazzini, Francesca aut Caruso, Francesca Pia aut Marzani, Francesco aut Solmonese, Laura aut Bello, Emma aut Celesti, Fabrizio aut Costa, Maria Claudia aut Noviello, Teresa aut Mortarini, Roberta aut Anichini, Andrea aut Ceccarelli, Michele aut Coral, Sandra aut Di Giacomo, Anna Maria aut Maio, Michele aut Covre, Alessia (orcid)0000-0001-8721-5693 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 22(2024), 1 vom: 01. März (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:22 year:2024 number:1 day:01 month:03 https://dx.doi.org/10.1186/s12967-024-05040-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 01 03 |
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10.1186/s12967-024-05040-x doi (DE-627)SPR054983819 (SPR)s12967-024-05040-x-e DE-627 ger DE-627 rakwb eng Lofiego, Maria Fortunata verfasserin aut Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Glioblastoma (dpeaa)DE-He213 Brain metastases (dpeaa)DE-He213 Immunotherapy (dpeaa)DE-He213 DNA hypomethylating agent (dpeaa)DE-He213 Melanoma (dpeaa)DE-He213 Piazzini, Francesca aut Caruso, Francesca Pia aut Marzani, Francesco aut Solmonese, Laura aut Bello, Emma aut Celesti, Fabrizio aut Costa, Maria Claudia aut Noviello, Teresa aut Mortarini, Roberta aut Anichini, Andrea aut Ceccarelli, Michele aut Coral, Sandra aut Di Giacomo, Anna Maria aut Maio, Michele aut Covre, Alessia (orcid)0000-0001-8721-5693 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 22(2024), 1 vom: 01. März (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:22 year:2024 number:1 day:01 month:03 https://dx.doi.org/10.1186/s12967-024-05040-x kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 01 03 |
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Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches |
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Lofiego, Maria Fortunata |
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Journal of translational medicine |
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Lofiego, Maria Fortunata Piazzini, Francesca Caruso, Francesca Pia Marzani, Francesco Solmonese, Laura Bello, Emma Celesti, Fabrizio Costa, Maria Claudia Noviello, Teresa Mortarini, Roberta Anichini, Andrea Ceccarelli, Michele Coral, Sandra Di Giacomo, Anna Maria Maio, Michele Covre, Alessia |
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Elektronische Aufsätze |
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Lofiego, Maria Fortunata |
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10.1186/s12967-024-05040-x |
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(ORCID)0000-0001-8721-5693 |
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title_sort |
epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches |
title_auth |
Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches |
abstract |
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. © The Author(s) 2024 |
abstractGer |
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. © The Author(s) 2024 |
abstract_unstemmed |
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. © The Author(s) 2024 |
collection_details |
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title_short |
Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches |
url |
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Piazzini, Francesca Caruso, Francesca Pia Marzani, Francesco Solmonese, Laura Bello, Emma Celesti, Fabrizio Costa, Maria Claudia Noviello, Teresa Mortarini, Roberta Anichini, Andrea Ceccarelli, Michele Coral, Sandra Di Giacomo, Anna Maria Maio, Michele Covre, Alessia |
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Piazzini, Francesca Caruso, Francesca Pia Marzani, Francesco Solmonese, Laura Bello, Emma Celesti, Fabrizio Costa, Maria Claudia Noviello, Teresa Mortarini, Roberta Anichini, Andrea Ceccarelli, Michele Coral, Sandra Di Giacomo, Anna Maria Maio, Michele Covre, Alessia |
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