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ATM activity in T cells is critical for immune surveillance of lymphoma in vivo

Leukemia volume 34, pages 771–786 (2020)Cite this article

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Abstract

The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients. Using T cell-specific Atm-knockout models, as well as allogeneic transplantation experiments, we pinpoint impaired immune surveillance as a contributor to cancer predisposition and development. Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. Altogether, our data indicate that T cell-specific restoration of ATM activity or allogeneic hematopoietic stem cell transplantation may prevent lymphomagenesis in A-T patients.

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Acknowledgements

This work was supported through the Cologne Center for Genomics of the University of Cologne. We thank Prof. Peter Nürnberg, Dr. Janine Altmüller and Dr. Graziella Bosco (University of Cologne, Germany) for help with RNA- and whole exome sequencing.

Financial support

This work was supported by the Volkswagenstiftung (Lichtenberg Program, HCR), the Deutsche Forschungsgemeinschaft (KFO-286, LPF and HCR, JA 2439/1-1 to RDJ), the Bundesministerium für Bildung und Forschung (SMOOSE, HCR), the German federal state NRW (EFRE initiative, LS-1-1-030a, HCR), the Else Kröner-Fresenius Stiftung (EKFS-2014-A06, HCR, 2016-Kolleg-19 to RDJ), the Deutsche Krebshilfe (111724, HCR) and the Jose Carreras Stiftung (DJCLS-R12/26, LPF and HCR).

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Author notes

  1. These authors contributed equally: Filippo Beleggia, Hans Christian Reinhardt

Authors and Affiliations

  1. Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany

    Arina Riabinska, Daria Lehrmann, Ron Daniel Jachimowicz, Gero Knittel, Christian Fritz, Anna Schmitt, Aenne Geyer, Lukas P. Frenzel, Alessandro Torgovnick, Filippo Beleggia & Hans Christian Reinhardt

  2. Department of Radiology, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany

    Carola Heneweer, Holger Grüll & Thorsten Persigehl

  3. Institute of Pathology, University Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany

    Maike Wittersheim, Monika Ortmann & Reinhard Büttner

  4. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50937, Germany

    Lukas P. Frenzel, Alessandro Torgovnick, Janica Lea Wiederstein, Marcus Krüger & Hans Christian Reinhardt

  5. Max Planck Institute for Metabolism Research, Cologne, 50937, Germany

    Claudia Maria Wunderlich & Frank Thomas Wunderlich

  6. Intitute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, 50937, Germany

    Arlette Paillard & Olaf Utermöhlen

  7. Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, 35390, Germany

    Wilhelm Wößmann

  8. Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Heinrich Heine University, Medical Faculty, Düsseldorf, 40225, Germany

    Arndt Borkhardt

  9. Children’s Cancer Research Center and Department of Pediatrics, Rechts der Isar Hospital, Technical University of Munich and Comprehensive Cancer Center Munich, Munich, 80333, Germany

    Stefan Burdach

  10. Institute of Pathology, University of Frankfurt, Medical School, Frankfurt, 60590, Germany

    Martin-Leo Hansmann

  11. Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, 97080, Germany

    Andreas Rosenwald

  12. Institute of Pathology, University Hospital Schleswig-Holstein, Lübeck, 23538, Germany

    Sven Perner

  13. Institute of Forensic Medicine, University Hospital Jena, Jena, 07743, Germany

    Gita Mall

  14. Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Kiel, 24105, Germany

    Wolfram Klapper

  15. Experimental Neurophysiology, German Center for Neurodegenerative Diseases, Bonn, 53175, Germany

    Andrea Merseburg

  16. Center for Molecular Medicine Cologne, University of Cologne, Cologne, 50937, Germany

    Martin Peifer, Olaf Utermöhlen, Reinhard Büttner & Hans Christian Reinhardt

  17. Department of Translational Genomics, Cologne, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany

    Martin Peifer

  18. German Center for Infection Research (DZIF), Bonn-Cologne, Cologne, Germany

    Olaf Utermöhlen

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  1. Arina Riabinska
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Correspondence to Arina Riabinska or Hans Christian Reinhardt.

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HCR received consulting fees from Abbvie, AstraZeneca, Vertex, and Merck and research funding from Gilead. The remaining authors declare that they have no conflict of interest.

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Riabinska, A., Lehrmann, D., Jachimowicz, R.D. et al. ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia 34, 771–786 (2020). https://doi.org/10.1038/s41375-019-0618-2

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