Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade
Immune-checkpoint inhibitors (ICI) are highly effective in reinvigorating T cells to attack cancer. Nevertheless, a large subset of patients fails to benefit from ICI, partly due to lack of the cancer neoepitopes necessary to trigger an immune response. In this study, we used the thiopurine 6-thiogu...
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| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2158610 |
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| author | Loulieta Nazerai Shona Caroline Willis Patricio Yankilevich Luca Di Leo Francesca Maria Bosisio Alex Frias Corine Bertolotto Jacob Nersting Maria Thastrup Soren Buus Allan Randrup Thomsen Morten Nielsen Kristoffer Staal Rohrberg Kjeld Schmiegelow Daniela De Zio |
| author_facet | Loulieta Nazerai Shona Caroline Willis Patricio Yankilevich Luca Di Leo Francesca Maria Bosisio Alex Frias Corine Bertolotto Jacob Nersting Maria Thastrup Soren Buus Allan Randrup Thomsen Morten Nielsen Kristoffer Staal Rohrberg Kjeld Schmiegelow Daniela De Zio |
| author_sort | Loulieta Nazerai |
| collection | DOAJ |
| description | Immune-checkpoint inhibitors (ICI) are highly effective in reinvigorating T cells to attack cancer. Nevertheless, a large subset of patients fails to benefit from ICI, partly due to lack of the cancer neoepitopes necessary to trigger an immune response. In this study, we used the thiopurine 6-thioguanine (6TG) to induce random mutations and thus increase the level of neoepitopes presented by tumor cells. Thiopurines are prodrugs which are converted into thioguanine nucleotides that are incorporated into DNA (DNA-TG), where they can induce mutation through single nucleotide mismatching. In a pre-clinical mouse model of a mutation-low melanoma cell line, we demonstrated that 6TG induced clinical-grade DNA-TG integration resulting in an improved tumor control that was strongly T cell dependent. 6TG exposure increased the tumor mutational burden, without affecting tumor cell proliferation and cell death. Moreover, 6TG treatment re-shaped the tumor microenvironment by increasing T and NK immune cells, making the tumors more responsive to immune-checkpoint blockade. We further validated that 6TG exposure improved tumor control in additional mouse models of melanoma. These findings have paved the way for a phase I/II clinical trial that explores whether treatment with thiopurines can increase the proportion of otherwise treatment-resistant cancer patients who may benefit from ICI therapy (NCT05276284). |
| format | Article |
| id | doaj-art-4dfe4b677ec94c7b9323ef328b78f448 |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-4dfe4b677ec94c7b9323ef328b78f4482025-08-20T02:50:44ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2022.2158610Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockadeLoulieta Nazerai0Shona Caroline Willis1Patricio Yankilevich2Luca Di Leo3Francesca Maria Bosisio4Alex Frias5Corine Bertolotto6Jacob Nersting7Maria Thastrup8Soren Buus9Allan Randrup Thomsen10Morten Nielsen11Kristoffer Staal Rohrberg12Kjeld Schmiegelow13Daniela De Zio14Melanoma Research Team, Danish Cancer Society Research Center, Copenhagen, DenmarkMelanoma Research Team, Danish Cancer Society Research Center, Copenhagen, DenmarkBioinformatics Core Facility, Instituto de Investigación En Biomedicina de Buenos Aires (Ibioba), Buenos Aires, ArgentinaMelanoma Research Team, Danish Cancer Society Research Center, Copenhagen, DenmarkLab of Translational Cell and Tissue Research, University of Leuven, Leuven, BelgiumMelanoma Research Team, Danish Cancer Society Research Center, Copenhagen, DenmarkUniversite Côte d’Azur, Nice, FranceDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkDepartment of Immunology and Microbiology, University of Copenhagen, Copenhagen, DenmarkDepartment of Immunology and Microbiology, University of Copenhagen, Copenhagen, DenmarkDepartment of Health Technology, Section for Bioinformatics, Technical University of Denmark, Lyngby, DenmarkDepartment of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkMelanoma Research Team, Danish Cancer Society Research Center, Copenhagen, DenmarkImmune-checkpoint inhibitors (ICI) are highly effective in reinvigorating T cells to attack cancer. Nevertheless, a large subset of patients fails to benefit from ICI, partly due to lack of the cancer neoepitopes necessary to trigger an immune response. In this study, we used the thiopurine 6-thioguanine (6TG) to induce random mutations and thus increase the level of neoepitopes presented by tumor cells. Thiopurines are prodrugs which are converted into thioguanine nucleotides that are incorporated into DNA (DNA-TG), where they can induce mutation through single nucleotide mismatching. In a pre-clinical mouse model of a mutation-low melanoma cell line, we demonstrated that 6TG induced clinical-grade DNA-TG integration resulting in an improved tumor control that was strongly T cell dependent. 6TG exposure increased the tumor mutational burden, without affecting tumor cell proliferation and cell death. Moreover, 6TG treatment re-shaped the tumor microenvironment by increasing T and NK immune cells, making the tumors more responsive to immune-checkpoint blockade. We further validated that 6TG exposure improved tumor control in additional mouse models of melanoma. These findings have paved the way for a phase I/II clinical trial that explores whether treatment with thiopurines can increase the proportion of otherwise treatment-resistant cancer patients who may benefit from ICI therapy (NCT05276284).https://www.tandfonline.com/doi/10.1080/2162402X.2022.2158610Thiopurine6TGimmune checkpoint inhibitorsmelanomamouse model |
| spellingShingle | Loulieta Nazerai Shona Caroline Willis Patricio Yankilevich Luca Di Leo Francesca Maria Bosisio Alex Frias Corine Bertolotto Jacob Nersting Maria Thastrup Soren Buus Allan Randrup Thomsen Morten Nielsen Kristoffer Staal Rohrberg Kjeld Schmiegelow Daniela De Zio Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade OncoImmunology Thiopurine 6TG immune checkpoint inhibitors melanoma mouse model |
| title | Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade |
| title_full | Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade |
| title_fullStr | Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade |
| title_full_unstemmed | Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade |
| title_short | Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade |
| title_sort | thiopurine 6tg treatment increases tumor immunogenicity and response to immune checkpoint blockade |
| topic | Thiopurine 6TG immune checkpoint inhibitors melanoma mouse model |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2158610 |
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