Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade

Autores
Nazerai, Loulieta; Willis, Shona Caroline; Yankilevich, Patricio; Di Leo, Luca; Bosisio, Francesca Maria; Frias, Alex; Bertolotto, Corine; Nersting, Jacob; Thastrup, Maria; Buus, Soren; Thomsen, Allan Randrup; Nielsen, Morten; Rohrberg, Kristoffer Staal; Schmiegelow, Kjeld; De Zio, Daniela
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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).
Fil: Nazerai, Loulieta. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; Dinamarca
Fil: Willis, Shona Caroline. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; Dinamarca
Fil: Yankilevich, Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Di Leo, Luca. Danish Cancer Society Research Center; Dinamarca
Fil: Bosisio, Francesca Maria. Katholikie Universiteit Leuven; Bélgica
Fil: Frias, Alex. Danish Cancer Society Research Center; Dinamarca
Fil: Bertolotto, Corine. Centre Méditerranéen de Médecine Moléculaire; Francia. Université Côte D'azur; Francia
Fil: Nersting, Jacob. Universidad de Copenhagen; Dinamarca
Fil: Thastrup, Maria. Universidad de Copenhagen; Dinamarca
Fil: Buus, Soren. Universidad de Copenhagen; Dinamarca
Fil: Thomsen, Allan Randrup. Universidad de Copenhagen; Dinamarca
Fil: Nielsen, Morten. Technical University of Denmark; Dinamarca
Fil: Rohrberg, Kristoffer Staal. Universidad de Copenhagen; Dinamarca
Fil: Schmiegelow, Kjeld. Universidad de Copenhagen; Dinamarca
Fil: De Zio, Daniela. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; Dinamarca
Materia
6TG
IMMUNE CHECKPOINT INHIBITORS
MELANOMA
MOUSE MODEL
THIOPURINE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/215198
Acceder
id CONICETDig_e5df3767dffba3da1ad91ed68e79f909
oai_identifier_str oai:ri.conicet.gov.ar:11336/215198
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockadeNazerai, LoulietaWillis, Shona CarolineYankilevich, PatricioDi Leo, LucaBosisio, Francesca MariaFrias, AlexBertolotto, CorineNersting, JacobThastrup, MariaBuus, SorenThomsen, Allan RandrupNielsen, MortenRohrberg, Kristoffer StaalSchmiegelow, KjeldDe Zio, Daniela6TGIMMUNE CHECKPOINT INHIBITORSMELANOMAMOUSE MODELTHIOPURINEhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Immune-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).Fil: Nazerai, Loulieta. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; DinamarcaFil: Willis, Shona Caroline. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; DinamarcaFil: Yankilevich, Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Di Leo, Luca. Danish Cancer Society Research Center; DinamarcaFil: Bosisio, Francesca Maria. Katholikie Universiteit Leuven; BélgicaFil: Frias, Alex. Danish Cancer Society Research Center; DinamarcaFil: Bertolotto, Corine. Centre Méditerranéen de Médecine Moléculaire; Francia. Université Côte D'azur; FranciaFil: Nersting, Jacob. Universidad de Copenhagen; DinamarcaFil: Thastrup, Maria. Universidad de Copenhagen; DinamarcaFil: Buus, Soren. Universidad de Copenhagen; DinamarcaFil: Thomsen, Allan Randrup. Universidad de Copenhagen; DinamarcaFil: Nielsen, Morten. Technical University of Denmark; DinamarcaFil: Rohrberg, Kristoffer Staal. Universidad de Copenhagen; DinamarcaFil: Schmiegelow, Kjeld. Universidad de Copenhagen; DinamarcaFil: De Zio, Daniela. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; DinamarcaTaylor & Francis2022-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/215198Nazerai, Loulieta; Willis, Shona Caroline; Yankilevich, Patricio; Di Leo, Luca; Bosisio, Francesca Maria; et al.; Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade; Taylor & Francis; OncoImmunology; 12; 1; 12-2022; 1-172162-40112162-402XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1080/2162402X.2022.2158610info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.1080/2162402X.2022.2158610info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:41:13Zoai:ri.conicet.gov.ar:11336/215198instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:41:13.733CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade
title Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade
spellingShingle Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade
Nazerai, Loulieta
6TG
IMMUNE CHECKPOINT INHIBITORS
MELANOMA
MOUSE MODEL
THIOPURINE
title_short 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_sort Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade
dc.creator.none.fl_str_mv Nazerai, Loulieta
Willis, Shona Caroline
Yankilevich, Patricio
Di Leo, Luca
Bosisio, Francesca Maria
Frias, Alex
Bertolotto, Corine
Nersting, Jacob
Thastrup, Maria
Buus, Soren
Thomsen, Allan Randrup
Nielsen, Morten
Rohrberg, Kristoffer Staal
Schmiegelow, Kjeld
De Zio, Daniela
author Nazerai, Loulieta
author_facet Nazerai, Loulieta
Willis, Shona Caroline
Yankilevich, Patricio
Di Leo, Luca
Bosisio, Francesca Maria
Frias, Alex
Bertolotto, Corine
Nersting, Jacob
Thastrup, Maria
Buus, Soren
Thomsen, Allan Randrup
Nielsen, Morten
Rohrberg, Kristoffer Staal
Schmiegelow, Kjeld
De Zio, Daniela
author_role author
author2 Willis, Shona Caroline
Yankilevich, Patricio
Di Leo, Luca
Bosisio, Francesca Maria
Frias, Alex
Bertolotto, Corine
Nersting, Jacob
Thastrup, Maria
Buus, Soren
Thomsen, Allan Randrup
Nielsen, Morten
Rohrberg, Kristoffer Staal
Schmiegelow, Kjeld
De Zio, Daniela
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv 6TG
IMMUNE CHECKPOINT INHIBITORS
MELANOMA
MOUSE MODEL
THIOPURINE
topic 6TG
IMMUNE CHECKPOINT INHIBITORS
MELANOMA
MOUSE MODEL
THIOPURINE
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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).
Fil: Nazerai, Loulieta. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; Dinamarca
Fil: Willis, Shona Caroline. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; Dinamarca
Fil: Yankilevich, Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Di Leo, Luca. Danish Cancer Society Research Center; Dinamarca
Fil: Bosisio, Francesca Maria. Katholikie Universiteit Leuven; Bélgica
Fil: Frias, Alex. Danish Cancer Society Research Center; Dinamarca
Fil: Bertolotto, Corine. Centre Méditerranéen de Médecine Moléculaire; Francia. Université Côte D'azur; Francia
Fil: Nersting, Jacob. Universidad de Copenhagen; Dinamarca
Fil: Thastrup, Maria. Universidad de Copenhagen; Dinamarca
Fil: Buus, Soren. Universidad de Copenhagen; Dinamarca
Fil: Thomsen, Allan Randrup. Universidad de Copenhagen; Dinamarca
Fil: Nielsen, Morten. Technical University of Denmark; Dinamarca
Fil: Rohrberg, Kristoffer Staal. Universidad de Copenhagen; Dinamarca
Fil: Schmiegelow, Kjeld. Universidad de Copenhagen; Dinamarca
Fil: De Zio, Daniela. Universidad de Copenhagen; Dinamarca. Danish Cancer Society Research Center; Dinamarca
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).
publishDate 2022
dc.date.none.fl_str_mv 2022-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/215198
Nazerai, Loulieta; Willis, Shona Caroline; Yankilevich, Patricio; Di Leo, Luca; Bosisio, Francesca Maria; et al.; Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade; Taylor & Francis; OncoImmunology; 12; 1; 12-2022; 1-17
2162-4011
2162-402X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/215198
identifier_str_mv Nazerai, Loulieta; Willis, Shona Caroline; Yankilevich, Patricio; Di Leo, Luca; Bosisio, Francesca Maria; et al.; Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade; Taylor & Francis; OncoImmunology; 12; 1; 12-2022; 1-17
2162-4011
2162-402X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1080/2162402X.2022.2158610
info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.1080/2162402X.2022.2158610
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Taylor & Francis
publisher.none.fl_str_mv Taylor & Francis
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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