Abstract

Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.

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Acknowledgements

HB was supported by Wilhelm-Sander Foundation, by the SFB TR 221 (project B12), and by the SFB 1181 (project B04) from the German Research Foundation. This research was also funded by Celgene and Morphosys. DD was funded by the IZKF Erlangen (project A65) DAV acknowledges research support by the German Research Foundation (DFG VO 1355/5-1) and the Alfried Krupp von Bohlen und Halbach-Stiftung. We would like to acknowledge the excellent assistance of the Core Unit Cell Sorting and Immunomonitoring Erlangen. The present work was performed in partial of the requirements for obtaining the degree “Dr. med”.

Author contributions

LB conceived project, designed the experiments, and wrote the manuscript. MB and DM designed and conducted experiments, helped writing manuscript. MBH selected and evaluated histopathological MM specimens established the immunohistochemical stainings. MJM, DAV, FN, and BS designed experiments and contributed to writing the manuscript. CB, SJ, and HB performed experiments. JN, SB, FB, DG, DD, KG, and FFH provided patient materials, analyzed data, and provided critical suggestions and discussions throughout the study. JTB, FN, RB, MF, CPP, and MH contributed essential reagents/analytical tools and scientific input. AM provided major intellectual input for project design, helped writing the manuscript. HB conceived and directed the project, wrote manuscript.

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Affiliations

  1. Department of Internal Medicine 5—Hematology/Oncology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

    • Leonhard Busch
    • , Dimitrios Mougiakakos
    • , Christian Bach
    • , Martin Böttcher
    • , Simon Jitschin
    • , Heidi Balzer
    • , Bernd Spriewald
    • , Andreas Mackensen
    •  & Heiko Bruns
  2. Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

    • Maike Büttner-Herold
  3. Institute of Bioanalytical Chemistry, Saarland University, Saarbrücken, Germany

    • Miriam J. Müller
    •  & Dietrich A. Volmer
  4. Department of Dermatology, University of Cologne, Cologne, Germany

    • Mario Fabri
  5. Medizinische Klinik I, Saarland University Medical School, Homburg/Saar, Germany

    • Jörg T. Bittenbring
    •  & Frank Neumann
  6. MorphoSys AG, Planegg, Germany

    • Rainer Boxhammer
  7. Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany

    • Jens Nolting
    •  & Savita Bisht
  8. Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

    • Markus H. Hoffmann
  9. Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Medical School, Aachen, Germany

    • Fabian Beier
    •  & Deniz Gezer
  10. Department of Dermatology, Laboratory of Dendritic Cell Biology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

    • Diana Dudziak
  11. Department of Trauma Surgery, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

    • Kolja Gelse
    •  & Friedrich F. Hennig
  12. Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

    • Christian P. Pallasch

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Conflict of interest

RB is an employee of Morphosys. HB received research support from Celgene and Morphosys. The remaining authors declare that they have no conflict of interest.

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Correspondence to Heiko Bruns.

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https://doi.org/10.1038/s41375-018-0114-0