Abstract
T cell-driven diseases account for considerable morbidity and disability globally and there is an urgent need for new targeted therapies. Both cancer cells and activated T cells have an altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs before the ROS levels increase, challenging the established conception of MTH1 increasing as a direct response to an increased ROS status. We also propose a heterogeneity in MTH1 levels among activated T cells, where a smaller subset of activated T cells does not up-regulate MTH1 despite activation and proliferation. The study suggests that the vast majority of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579 (Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the surviving cells to the MTH1low phenotype with altered redox status. TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. Finally, we demonstrate a therapeutic effect in a murine model of experimental autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of MTH1high and MTH1low activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis.
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Acknowledgements
We thank our chemists Martin Scobie, Tobias Koolmeister, Olov Wallner and Martin Henriksson for all the work on the chemistry side, not the least synthesizing the MTH1 inhibitors. We thank Nadilly Bonagas and Aleksandra Pettke for valuable methodological input and all the members of the Helleday laboratory for discussion and support. We thank Weng-Onn Lui at the flow cytometry lab of the Department of Oncology-Pathology for technical assistance and support.
Funding
This work was funded by Karolinska Institute via its CSTP program and research internship program (forskar-AT), The European Research Council (TAROX Programme, ERC-695376, TH), The Swedish Research Council (2015-00162, 2017-06095), and the Torsten and Ragnar Söderberg Foundation (TH).
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RF, SK, TH, and UWB devised the concept of the study; UWB, RF, KC, CK, and LB supervised the project. SK, RF, PM, MMS, CS, KS, KC, IA, and CK designed, performed and/or analyzed cell biological experiments. XZ, RH, SK, AR, TP, KC, CS, BP, UWB designed, performed and/or analyzed in vivo experiments. SK compiled data and prepared the figures; SK drafted the manuscript supervised by UWB, CK, and TH; all authors reviewed the final manuscript.
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A patent has been filed with data generated in this manuscript, where TH is listed as one of the inventors. The patent is fully owned by a non-profit public foundation, the Helleday Foundation for medical research (THF), and TH and UWB are members of THF board. Oxcia AB has license to the patent and perform clinical development of TH1579. UWB is CEO of Oxcia AB, TH is board member of Oxcia AB. The other authors declare no conflict of interest.
Ethics approval
This study was performed in accordance with the Declaration of Helsinki. The in vitro experiments on human T cells were performed on products from buffy coats extracted from blood products donated by healthy donors for the blood banks of the Karolinska University Hospital (Stockholm, Sweden), where no additional intervention was performed on the donors specifically for this research. There was no possibility to trace back the samples to the donors. The in vivo studies were approved by the local ethical committees (Stockholm North, number N138/14 for the EAE study; Stockholm South, number S7-15 for the TDAR study).
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Karsten, S., Fiskesund, R., Zhang, XM. et al. MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells. Cell Death Differ 29, 246–261 (2022). https://doi.org/10.1038/s41418-021-00854-4
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DOI: https://doi.org/10.1038/s41418-021-00854-4
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