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Mechanism of tumor remission by cytomegalovirus in a murine lymphoma model: evidence for involvement of virally induced cellular interleukin-15

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Abstract

A murine model of B and T cell lymphomas in recipients after hematoablative conditioning for hematopoietic cell transplantation (HCT) has previously revealed a tumor-repressive, metastasis-inhibiting function of murine cytomegalovirus (mCMV). More recently, this prediction from the experimental model was put on trial in several clinical studies that indeed gave evidence for a lower incidence of tumor relapse associated with early reactivation of latent human cytomegalovirus (hCMV) after allogeneic HCT in patients treated against different types of hematopoietic malignancies, including lymphoma and acute as well as chronic leukemias. Due to the limitations inherent to clinical studies, the tumor-repressive role of hCMV remained observational with no approach to clarify mechanisms. Although the tumor-repressive mechanisms of mCMV and hCMV may differ and depend on the type of tumor, experimental approaches in the murine model might give valuable hints for concepts to follow in clinical research. We have previously shown for the liver-adapted A20-derived B cell lymphoma E12E that mCMV does not infect the lymphoma cells for causing cell death by viral cytopathogenicity but triggers tumor-selective apoptosis at a tissue site of tumor metastasis distant from a local site of infection. This finding suggested involvement of a cytokine that triggers apoptosis, directly or indirectly. Here we used a series of differential high-density microarray analyses to identify cellular genes whose expression is specifically upregulated at the site of virus entry only by viruses capable of triggering lymphoma cell apoptosis. This strategy identified interleukin-15 (IL-15) as most promising candidate, eventually confirmed by lymphoma repression with recombinant IL-15.

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft, collaborative research grant SFB432, individual project A10 ‘Influence of cytomegalovirus infection on the risk of leukemia relapse after HCT’, and the Clinical Research Group KFO183. The authors thank the team of the High Density Microarray (HDMA) Core Facility of the SFB432, central project Z6 (Özlem Türeci and Ulrich Luxemburger) for having expertly performed the HDMA analyses with all quality controls, and for advice in data interpretation.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

All procedures performed in studies involving animals were approved by the ethics committee of the Landesuntersuchungsamt Rheinland-Pfalz, permission no. 1.5 177-07-04/051-56 in accordance with German Federal Law §8 Abs. 1 TierSchG (animal protection law). BALB/c mice and H-2d;BALB-RAG2γc mice were bred and housed under specified pathogen-free conditions at the Central Laboratory Animal Facility (CLAF) at the University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

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  1. Katja C. Erlach

    Present address: Roche Diagnostics Deutschland GmbH, Sandhofer Strasse 116, 68305, Mannheim, Germany

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  1. Institute for Virology, University Medical Center of the Johannes Gutenberg-University Mainz and Research Center for Immunotherapy (FZI), Obere Zahlbacher Strasse 67, Hochhaus am Augustusplatz, 55131, Mainz, Germany

    Katja C. Erlach, Matthias J. Reddehase & Jürgen Podlech

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  1. Katja C. Erlach
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Correspondence to Jürgen Podlech.

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This article is part of the Special Issue on Cytomegalovirus.

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Erlach, K.C., Reddehase, M.J. & Podlech, J. Mechanism of tumor remission by cytomegalovirus in a murine lymphoma model: evidence for involvement of virally induced cellular interleukin-15. Med Microbiol Immunol 204, 355–366 (2015). https://doi.org/10.1007/s00430-015-0408-z

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