Artículo
Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade
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
Fecha de publicación:
12/2022
Editorial:
Taylor & Francis
Revista:
OncoImmunology
ISSN:
2162-4011
e-ISSN:
2162-402X
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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).
Palabras clave:
6TG
,
IMMUNE CHECKPOINT INHIBITORS
,
MELANOMA
,
MOUSE MODEL
,
THIOPURINE
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Identificadores
Colecciones
Articulos(IBIOBA - MPSP)
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Citación
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
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