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

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*

*Corresponding author for this work

Abstract

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).

Original languageEnglish
Article number2158610
JournalOncoImmunology
Volume12
Issue number1
ISSN2162-4011
DOIs
Publication statusPublished - 2023

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