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...
| Autores: | , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/116517 |
| Acceso en línea: | https://hdl.handle.net/10171/116517 |
| Access Level: | acceso abierto |
| Palabra clave: | Melanoma Cancer vaccination Dendritic cell vaccination Adoptive T cell therapies Epigenetic targeted therapy Histone and DNA methylation/demethylation Histone methyltransferase G9a DNA methyltransferase (DNMT) |
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Inhibiting histone and DNA methylation improves cancer vaccination in an experimental model of melanomaDe-Beck, L. (Lien)|||/items/29101c5e-3eaa-4306-8e20-a4290afa3192Awad, R.M. (Robin Maximilian)|||/items/1087d86e-29ee-4592-a4ab-9eac69d921d7Basso, V. (Veronica)|||/items/cd7daa55-e25c-45ae-bce7-79b01f7712c2Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7bDe-Ridder, K. (Kirsten)|||/items/19fcf443-dd65-4fe0-8ee8-dd30a6322164De-Vlaeminck, Y. (Yannick)|||/items/9a5ae9bd-608a-4f8e-a7f1-d663d526aa66Gnata, A. (Alessandra)|||/items/b4c543c9-21b1-4520-9c1b-f6e02ced54beGoyvaerts, C. (Cleo)|||/items/74c60779-b765-4223-85ae-e927a5b4f2a2Lecocq, Q. (Quentin)|||/items/42c2cfb5-c303-4504-8068-d641f030efa0San-José-Enériz, E. (Edurne)|||/items/1c6714b1-f536-4b57-a755-83eca42e9964Verhulst, S. (Stefaan)|||/items/ed541fbd-0664-4d30-967f-d481b35924f9Maes, K. (Ken)|||/items/9af6494a-db92-4001-9073-634cc84ae902Vanderkerken, K. (Karin)|||/items/afb22f0b-34a8-4e49-84bb-52ad550bf66aProsper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0cMondino, A. (Anna)|||/items/526c1918-c5a1-4858-a84c-20c6d69ff79aBreckpot, K. (Karine)|||/items/a8a26dbc-ff97-4670-aa0f-fe536be9ff1bAguirre-Ena, X. (Xabier)|||/items/2a000d9c-cb5c-4734-a32c-4fef79998c86MelanomaCancer vaccinationDendritic cell vaccinationAdoptive T cell therapiesEpigenetic targeted therapyHistone and DNA methylation/demethylationHistone methyltransferase G9aDNA methyltransferase (DNMT)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.Frontiers Media S.A.Dadun. Depósito Académico Digital Universidad de Navarra20222022-01-0120222022-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/116517reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1165172026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Inhibiting histone and DNA methylation improves cancer vaccination in an experimental model of melanoma |
| title |
Inhibiting histone and DNA methylation improves cancer vaccination in an experimental model of melanoma |
| spellingShingle |
Inhibiting histone and DNA methylation improves cancer vaccination in an experimental model of melanoma De-Beck, L. (Lien)|||/items/29101c5e-3eaa-4306-8e20-a4290afa3192 Melanoma Cancer vaccination Dendritic cell vaccination Adoptive T cell therapies Epigenetic targeted therapy Histone and DNA methylation/demethylation Histone methyltransferase G9a DNA methyltransferase (DNMT) |
| title_short |
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_sort |
Inhibiting histone and DNA methylation improves cancer vaccination in an experimental model of melanoma |
| dc.creator.none.fl_str_mv |
De-Beck, L. (Lien)|||/items/29101c5e-3eaa-4306-8e20-a4290afa3192 Awad, R.M. (Robin Maximilian)|||/items/1087d86e-29ee-4592-a4ab-9eac69d921d7 Basso, V. (Veronica)|||/items/cd7daa55-e25c-45ae-bce7-79b01f7712c2 Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7b De-Ridder, K. (Kirsten)|||/items/19fcf443-dd65-4fe0-8ee8-dd30a6322164 De-Vlaeminck, Y. (Yannick)|||/items/9a5ae9bd-608a-4f8e-a7f1-d663d526aa66 Gnata, A. (Alessandra)|||/items/b4c543c9-21b1-4520-9c1b-f6e02ced54be Goyvaerts, C. (Cleo)|||/items/74c60779-b765-4223-85ae-e927a5b4f2a2 Lecocq, Q. (Quentin)|||/items/42c2cfb5-c303-4504-8068-d641f030efa0 San-José-Enériz, E. (Edurne)|||/items/1c6714b1-f536-4b57-a755-83eca42e9964 Verhulst, S. (Stefaan)|||/items/ed541fbd-0664-4d30-967f-d481b35924f9 Maes, K. (Ken)|||/items/9af6494a-db92-4001-9073-634cc84ae902 Vanderkerken, K. (Karin)|||/items/afb22f0b-34a8-4e49-84bb-52ad550bf66a Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1 Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0c Mondino, A. (Anna)|||/items/526c1918-c5a1-4858-a84c-20c6d69ff79a Breckpot, K. (Karine)|||/items/a8a26dbc-ff97-4670-aa0f-fe536be9ff1b Aguirre-Ena, X. (Xabier)|||/items/2a000d9c-cb5c-4734-a32c-4fef79998c86 |
| author |
De-Beck, L. (Lien)|||/items/29101c5e-3eaa-4306-8e20-a4290afa3192 |
| author_facet |
De-Beck, L. (Lien)|||/items/29101c5e-3eaa-4306-8e20-a4290afa3192 Awad, R.M. (Robin Maximilian)|||/items/1087d86e-29ee-4592-a4ab-9eac69d921d7 Basso, V. (Veronica)|||/items/cd7daa55-e25c-45ae-bce7-79b01f7712c2 Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7b De-Ridder, K. (Kirsten)|||/items/19fcf443-dd65-4fe0-8ee8-dd30a6322164 De-Vlaeminck, Y. (Yannick)|||/items/9a5ae9bd-608a-4f8e-a7f1-d663d526aa66 Gnata, A. (Alessandra)|||/items/b4c543c9-21b1-4520-9c1b-f6e02ced54be Goyvaerts, C. (Cleo)|||/items/74c60779-b765-4223-85ae-e927a5b4f2a2 Lecocq, Q. (Quentin)|||/items/42c2cfb5-c303-4504-8068-d641f030efa0 San-José-Enériz, E. (Edurne)|||/items/1c6714b1-f536-4b57-a755-83eca42e9964 Verhulst, S. (Stefaan)|||/items/ed541fbd-0664-4d30-967f-d481b35924f9 Maes, K. (Ken)|||/items/9af6494a-db92-4001-9073-634cc84ae902 Vanderkerken, K. (Karin)|||/items/afb22f0b-34a8-4e49-84bb-52ad550bf66a Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1 Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0c Mondino, A. (Anna)|||/items/526c1918-c5a1-4858-a84c-20c6d69ff79a Breckpot, K. (Karine)|||/items/a8a26dbc-ff97-4670-aa0f-fe536be9ff1b Aguirre-Ena, X. (Xabier)|||/items/2a000d9c-cb5c-4734-a32c-4fef79998c86 |
| author_role |
author |
| author2 |
Awad, R.M. (Robin Maximilian)|||/items/1087d86e-29ee-4592-a4ab-9eac69d921d7 Basso, V. (Veronica)|||/items/cd7daa55-e25c-45ae-bce7-79b01f7712c2 Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7b De-Ridder, K. (Kirsten)|||/items/19fcf443-dd65-4fe0-8ee8-dd30a6322164 De-Vlaeminck, Y. (Yannick)|||/items/9a5ae9bd-608a-4f8e-a7f1-d663d526aa66 Gnata, A. (Alessandra)|||/items/b4c543c9-21b1-4520-9c1b-f6e02ced54be Goyvaerts, C. (Cleo)|||/items/74c60779-b765-4223-85ae-e927a5b4f2a2 Lecocq, Q. (Quentin)|||/items/42c2cfb5-c303-4504-8068-d641f030efa0 San-José-Enériz, E. (Edurne)|||/items/1c6714b1-f536-4b57-a755-83eca42e9964 Verhulst, S. (Stefaan)|||/items/ed541fbd-0664-4d30-967f-d481b35924f9 Maes, K. (Ken)|||/items/9af6494a-db92-4001-9073-634cc84ae902 Vanderkerken, K. (Karin)|||/items/afb22f0b-34a8-4e49-84bb-52ad550bf66a Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1 Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0c Mondino, A. (Anna)|||/items/526c1918-c5a1-4858-a84c-20c6d69ff79a Breckpot, K. (Karine)|||/items/a8a26dbc-ff97-4670-aa0f-fe536be9ff1b Aguirre-Ena, X. (Xabier)|||/items/2a000d9c-cb5c-4734-a32c-4fef79998c86 |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Melanoma Cancer vaccination Dendritic cell vaccination Adoptive T cell therapies Epigenetic targeted therapy Histone and DNA methylation/demethylation Histone methyltransferase G9a DNA methyltransferase (DNMT) |
| topic |
Melanoma Cancer vaccination Dendritic cell vaccination Adoptive T cell therapies Epigenetic targeted therapy Histone and DNA methylation/demethylation Histone methyltransferase G9a DNA methyltransferase (DNMT) |
| 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. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022-01-01 2022 2022-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/116517 |
| url |
https://hdl.handle.net/10171/116517 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Frontiers Media S.A. |
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Frontiers Media S.A. |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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1869402884063363072 |
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15.812429 |