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Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked

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Abstract

Background

There is limited understanding of the dysregulation of the innate immune system in multiple myeloma (MM). We analysed the expression of the activating receptor NKG2D on NK cells and T cells of MM patients and investigated the impact of soluble versus membrane-bound NKG2D ligands on the expression of NKG2D.

Design

NKG2D expression on NK cells and CD8+ αβ T cells from patients with MM or monoclonal gammopathy of uncertain significance and healthy controls was examined flow-cytometrically. Sera from patients and controls were analysed for soluble NKG2D ligands (sNKG2D ligands).

Results

Significantly fewer NK cells and CD8+ αβ T cells from patients expressed NKG2D compared to healthy controls (NK cells: median 54% interquartile range (IQR) 32–68 versus 71% IQR 44–82%, P = 0.017, CD8+ αβ T cells: median 63% IQR 52–81 versus 77% IQR 71–90%, P = 0.018). The sNKG2D ligand sMICA was increased in patients [median 175 (IQR 87–295) pg/ml] versus controls [median 80 (IQR 32–129) pg/ml, P < 0.001], but levels of sMICA did not correlate with NKG2D expression on effector cells. To elucidate the mechanism of NKG2D down-regulation, we incubated lymphocytes from healthy donors in the presence of sNKG2D ligands or in co-culture with MM cell lines. sNKG2D ligands in clinically relevant concentrations did not down-regulate NKG2D expression, but co-culture of effector cells with myeloma cells with high surface expression of NKG2D ligands reduced NKG2D expression significantly.

Conclusions

These results indicate that MM is associated with a significant reduction in NKG2D expression which may be contact-mediated rather than caused by soluble NKG2D ligands.

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Acknowledgments

The authors would like to thank Annette Brause and Andrea Linke for excellent technical assistance and the Institut für Experimentelle Hämatologie und Transfusionsmedizin, Universitätsklinikum Bonn, Germany, for providing buffy coats. MvLT is supported by an EBMT Amgen fellowship and by a grant from BONFOR research foundation. SF is supported by the Arnold Tunstall Research Fellowship, British Society for Haematology and the Leukaemia Research Fund.

Conflict of interest statement

The authors have no conflict of interest to disclose.

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Authors and Affiliations

  1. Transplant Immunology Group, Level 3, St. James’s Institute of Oncology, Bexley Wing, St James’s University Hospital, Leeds, LS9 7TF, UK

    Marie von Lilienfeld-Toal, Sylvia Feyler, Sarah Jarmin & Gordon Cook

  2. Medizinische Klinik und Poliklinik III, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany

    Marie von Lilienfeld-Toal, Susanne Frank, Christiane Leyendecker, Axel Glasmacher, Ingo G. H. Schmidt-Wolf & Peter Brossart

  3. Cancer Research UK, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK

    Ruth Morgan

  4. Universitätsklinik Heidelberg, Heidelberg, Germany

    Angela Märten

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  1. Marie von Lilienfeld-Toal
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  2. Susanne Frank
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Corresponding author

Correspondence to Gordon Cook.

Additional information

M. von Lilienfeld-Toal and S. Frank contributed equally to the paper.

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von Lilienfeld-Toal, M., Frank, S., Leyendecker, C. et al. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother 59, 829–839 (2010). https://doi.org/10.1007/s00262-009-0807-3

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  • DOI: https://doi.org/10.1007/s00262-009-0807-3

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