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

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  • Loulieta Nazerai
  • Shona Caroline Willis
  • Patricio Yankilevich
  • Luca Di Leo
  • Francesca Maria Bosisio
  • Alex Frias
  • Corine Bertolotto
  • Jacob Nersting
  • Maria Thastrup
  • Buus, Søren
  • Thomsen, Allan Randrup
  • Morten Nielsen
  • Kristoffer Staal Rohrberg
  • Schmiegelow, K.
  • Daniela De Zio

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).

Udgave nummer1
Antal sider16
StatusUdgivet - 2023

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© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.

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