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DNA lesions correlate with lymphocyte function after selective internal radiotherapy

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Abstract

In patients with non-resectable hepatic malignancies selective internal radiotherapy (SIRT) with yttrium-90 is an effective therapy. However, previous data indicate that SIRT leads to impaired immune function. The aim of the current study was to determine the extent of DNA lesions in peripheral blood mononuclear cells of SIRT patients and to correlate these lesions with cellular immune responses. In ten patients γH2AX and 53BP1 foci were determined. These foci are markers of DNA double-strand breaks (DSBs) and occur consecutively. In parallel, lymphocyte proliferation was assessed after stimulation with the T cell mitogen phytohemagglutinin. Analyses of vital cells were performed prior to and 1 h and 1 week after SIRT. 1 h and 1 week after SIRT numbers of γH2AX and of 53BP1 foci were more than threefold larger than before (p < 0.01). Already at baseline, foci were more abundant than published in healthy controls. Lymphocyte proliferation at baseline was below the normal range and further decreased after SIRT. Prior to therapy, there was an inverse correlation between lymphocyte proliferation and the quotient 53BP1/γH2AX; which could be considered as a measure of the course of DNA DSB repair (r = − 0.94, p < 0.0001). Proliferative responses were inversely correlated with 53BP1 foci prior to therapy and γH2AX and 53BP1 foci 1 h after therapy (r < − 0.65, p < 0.05). In conclusion, DNA foci in SIRT patients were correlated with impaired in vitro immune function. Unrepaired DNA DSBs or cell cycle arrest due to repair may cause this impairment.

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Abbreviations

DSB:

Double strand break

LTT:

Lymphocyte transformation test

H2AX:

Protein histone 2A family member X

SIRT:

Selective internal radiotherapy

53BP1:

Tumor suppressor p53-binding protein 1

90Y:

Yttrium-90

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Acknowledgements

γH2AX and 53PB1 immunofluorescence stainings were kindly performed free of charge by Caroline Eberle, Lisa Heiserich and Peter Bauer (Medipan, Berlin, Germany). This article is a partial fulfilment of requirements for the doctor’s degree at the Medical Faculty, University of Duisburg-Essen, for Aglaia Domouchtsidou. The authors would like to thank Monika Huben and Martina Praast for their excellent technical assistance.

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Authors and Affiliations

  1. Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147, Essen, Germany

    Aglaia Domouchtsidou, Peter A. Horn & Monika Lindemann

  2. Institute of Nuclear Medicine, Helios Kliniken, Schwerin, Germany

    Vahé Barsegian

  3. Department of Nuclear Medicine, University Hospital, Essen, Germany

    Stefan P. Mueller & Andreas Bockisch

  4. Advanced Analytical Technologies, Melbourne, Australia

    Pavel Lobachevsky

  5. Department of Gastroenterology and Hepatology, University Hospital, Essen, Germany

    Jan Best

  6. Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

    Jan Best

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  1. Aglaia Domouchtsidou
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  8. Monika Lindemann
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Contributions

ML, VB, SPM, PL, AD, PAH and AB contributed to the conception and design of the study. AD and JB recruited the patients and took blood samples. AD performed the cellular in vitro assays. AD, PL and ML wrote the report. All authors critically revised and approved the final manuscript.

Corresponding author

Correspondence to Monika Lindemann.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

The study was institutional review board approved by the ethics committee of the Medical Faculty, University Hospital Essen (approval number 09-3991), and carried out in accordance with the 1964 Helsinki Declaration.

Informed consent

All participants provided written informed consent prior to their inclusion in the study.

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This study continues a study published previously (Domouchtsidou A, Barsegian V, Mueller SP, Best J, Ertle J, Bedreli S, et al. Impaired lymphocyte function in patients with hepatic malignancies after selective internal radiotherapy. Cancer Immunol Immunother. 2018;67:843–853).

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Domouchtsidou, A., Barsegian, V., Mueller, S.P. et al. DNA lesions correlate with lymphocyte function after selective internal radiotherapy. Cancer Immunol Immunother 68, 907–915 (2019). https://doi.org/10.1007/s00262-019-02323-x

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  • DOI: https://doi.org/10.1007/s00262-019-02323-x

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