Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma
Immunotherapy has improved the treatment of malignant skin cancer of the melanoma type, yet overall clinical response rates remain low. Combination therapies could be key to meet this cogent medical need. Because epigenetic hallmarks represent promising combination therapy targets, we studied the im...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.799636/full |
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| author | Lien De Beck Lien De Beck Robin Maximilian Awad Veronica Basso Noelia Casares Kirsten De Ridder Yannick De Vlaeminck Alessandra Gnata Cleo Goyvaerts Quentin Lecocq Edurne San José-Enériz Stefaan Verhulst Ken Maes Ken Maes Karin Vanderkerken Xabier Agirre Xabier Agirre Felipe Prosper Felipe Prosper Felipe Prosper Juan José Lasarte Anna Mondino Karine Breckpot |
| author_facet | Lien De Beck Lien De Beck Robin Maximilian Awad Veronica Basso Noelia Casares Kirsten De Ridder Yannick De Vlaeminck Alessandra Gnata Cleo Goyvaerts Quentin Lecocq Edurne San José-Enériz Stefaan Verhulst Ken Maes Ken Maes Karin Vanderkerken Xabier Agirre Xabier Agirre Felipe Prosper Felipe Prosper Felipe Prosper Juan José Lasarte Anna Mondino Karine Breckpot |
| author_sort | Lien De Beck |
| collection | DOAJ |
| description | Immunotherapy has improved the treatment of malignant skin cancer of the melanoma type, yet overall clinical response rates remain low. Combination therapies could be key to meet this cogent medical need. Because epigenetic hallmarks represent promising combination therapy targets, we studied the immunogenic potential of a dual inhibitor of histone methyltransferase G9a and DNA methyltransferases (DNMTs) in the preclinical B16-OVA melanoma model. Making use of tumor transcriptomic and functional analyses, methylation-targeted epigenetic reprogramming was shown to induce tumor cell cycle arrest and apoptosis in vitro coinciding with transient tumor growth delay and an IFN-I response in immune-competent mice. In consideration of a potential impact on immune cells, the drug was shown not to interfere with dendritic cell maturation or T-cell activation in vitro. Notably, the drug promoted dendritic cell and, to a lesser extent, T-cell infiltration in vivo, yet failed to sensitize tumor cells to programmed cell death-1 inhibition. Instead, it increased therapeutic efficacy of TCR-redirected T cell and dendritic cell vaccination, jointly increasing overall survival of B16-OVA tumor-bearing mice. The reported data confirm the prospect of methylation-targeted epigenetic reprogramming in melanoma and sustain dual G9a and DNMT inhibition as a strategy to tip the cancer-immune set-point towards responsiveness to active and adoptive vaccination against melanoma. |
| first_indexed | 2024-04-13T08:49:25Z |
| format | Article |
| id | doaj.art-f6044c9296d648419688c29e75e4e1a4 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T08:49:25Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f6044c9296d648419688c29e75e4e1a42022-12-22T02:53:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.799636799636Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of MelanomaLien De Beck0Lien De Beck1Robin Maximilian Awad2Veronica Basso3Noelia Casares4Kirsten De Ridder5Yannick De Vlaeminck6Alessandra Gnata7Cleo Goyvaerts8Quentin Lecocq9Edurne San José-Enériz10Stefaan Verhulst11Ken Maes12Ken Maes13Karin Vanderkerken14Xabier Agirre15Xabier Agirre16Felipe Prosper17Felipe Prosper18Felipe Prosper19Juan José Lasarte20Anna Mondino21Karine Breckpot22Laboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumLaboratory of Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumLaboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumLymphocyte Activation Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, ItalyImmunology and Immunotherapy Program, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, SpainLaboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumLaboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumLymphocyte Activation Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, ItalyLaboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumLaboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumHemato-Oncology Program, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, SpainLiver Cell Biology Research Group, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumLaboratory of Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumCenter for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, BelgiumLaboratory of Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumHemato-Oncology Program, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, SpainLaboratory of Cancer Epigenetics, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, SpainHemato-Oncology Program, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, SpainLaboratory of Cancer Epigenetics, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, SpainHematology and Cell Therapy Department, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, SpainImmunology and Immunotherapy Program, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, SpainLymphocyte Activation Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, ItalyLaboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussels, BelgiumImmunotherapy has improved the treatment of malignant skin cancer of the melanoma type, yet overall clinical response rates remain low. Combination therapies could be key to meet this cogent medical need. Because epigenetic hallmarks represent promising combination therapy targets, we studied the immunogenic potential of a dual inhibitor of histone methyltransferase G9a and DNA methyltransferases (DNMTs) in the preclinical B16-OVA melanoma model. Making use of tumor transcriptomic and functional analyses, methylation-targeted epigenetic reprogramming was shown to induce tumor cell cycle arrest and apoptosis in vitro coinciding with transient tumor growth delay and an IFN-I response in immune-competent mice. In consideration of a potential impact on immune cells, the drug was shown not to interfere with dendritic cell maturation or T-cell activation in vitro. Notably, the drug promoted dendritic cell and, to a lesser extent, T-cell infiltration in vivo, yet failed to sensitize tumor cells to programmed cell death-1 inhibition. Instead, it increased therapeutic efficacy of TCR-redirected T cell and dendritic cell vaccination, jointly increasing overall survival of B16-OVA tumor-bearing mice. The reported data confirm the prospect of methylation-targeted epigenetic reprogramming in melanoma and sustain dual G9a and DNMT inhibition as a strategy to tip the cancer-immune set-point towards responsiveness to active and adoptive vaccination against melanoma.https://www.frontiersin.org/articles/10.3389/fimmu.2022.799636/fullmelanomacancer vaccinationdendritic cell vaccinationadoptive T cell therapiesepigenetic targeted therapyhistone and DNA methylation/demethylation |
| spellingShingle | Lien De Beck Lien De Beck Robin Maximilian Awad Veronica Basso Noelia Casares Kirsten De Ridder Yannick De Vlaeminck Alessandra Gnata Cleo Goyvaerts Quentin Lecocq Edurne San José-Enériz Stefaan Verhulst Ken Maes Ken Maes Karin Vanderkerken Xabier Agirre Xabier Agirre Felipe Prosper Felipe Prosper Felipe Prosper Juan José Lasarte Anna Mondino Karine Breckpot Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma Frontiers in Immunology melanoma cancer vaccination dendritic cell vaccination adoptive T cell therapies epigenetic targeted therapy histone and DNA methylation/demethylation |
| title | Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma |
| title_full | Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma |
| title_fullStr | Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma |
| title_full_unstemmed | Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma |
| title_short | Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma |
| title_sort | inhibiting histone and dna methylation improves cancer vaccination in an experimental model of melanoma |
| topic | melanoma cancer vaccination dendritic cell vaccination adoptive T cell therapies epigenetic targeted therapy histone and DNA methylation/demethylation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.799636/full |
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