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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Bibliographic Details
Authors: 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
Format: article
Status:Published version
Publication Date:2022
Country:Argentina
Institution:Consejo Nacional de Investigaciones Científicas y Técnicas
Repository:CONICET Digital (CONICET)
Language:English
OAI Identifier:oai:ri.conicet.gov.ar:11336/215198
Online Access:http://hdl.handle.net/11336/215198
Access Level:Open access
Keyword:6TG
IMMUNE CHECKPOINT INHIBITORS
MELANOMA
MOUSE MODEL
THIOPURINE
https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
Description
Summary: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).

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