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The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells

Leukemia volume 29, pages 1213–1218 (2015)Cite this article

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Classical Hodgkin lymphoma (HL) is a common lymphoid malignancy that displays unique features with respect to morphology, tumor biology and clinical presentation. Histologically, classical HL is characterized by large mononuclear Hodgkin and multinucleated Reed–Sternberg (HRS) cells. A hallmark of HL cells is the highly inflammatory phenotype. Typically, the malignant HRS cells represent only a minor fraction of the affected lymph nodes and are surrounded by numerous benign reactive cells, including lymphocytes, macrophages and granulocytes. These inflammatory cells are attracted by cytokines and chemokines secreted by the malignant cell population.1, 2 The complex interactions between HRS cells and bystander cells create a specific microenvironment that is thought to be critical for growth and survival of HRS cells. A detailed analysis of signals evoked by these interactions does not only contribute to a better understanding of HL pathogenesis, but might also provide a basis for the development of new treatment strategies. Here, we describe an aberrant expression and activity of the interleukin 15 (IL-15) cytokine/cytokine receptor system in HL resulting in mitogenic and anti-apoptotic signals, as well as the enhanced expression of inflammatory factors by HRS cells. IL-15 is a pro-inflammatory cytokine that was originally identified through its ability to induce T-cell proliferation, displaying IL-2-like properties.3 Indeed, both cytokines act through a heterotrimeric receptor that shares the IL-2 receptor β (IL-2Rβ, also referred to as IL-15Rβ, CD122) and the common γ chain (IL-2Rγ, CD132). However, high-affinity binding specificity for each ligand is conferred by a unique subunit, namely IL-2Rα and IL-15Rα, respectively.3 Functionally, IL-15 has a pivotal role in the differentiation and/or survival of natural killer (NK) cells, NK T cells as well as intraepithelial lymphocytes and is critical for the maintenance of CD8+ memory T cells.4

To investigate the expression of IL-15 in primary HL cases, we performed immunohistochemical staining on frozen sections of control and HL tissue samples. Immunohistochemistry of nonmalignant reactive tonsils demonstrated specific staining for IL-15 predominantly in cells displaying macrophage or dendritic cell morphology, a feature that was particularly apparent in germinal centers, most likely corresponding to follicular dendritic cells,5 whereas germinal center B cells themselves were negative (Figure 1c). Moreover, immunohistochemistry revealed IL-15 expression in HRS cells in a series of eight primary HL cases with variable percentages of positive cells (Figure 1c; Supplementary Table 1). In addition, cells of the tumor microenvironment stained positive for IL-15, including cells with monocytic/dendritic morphology and endothelial cells, which is in accordance with previous studies describing IL-15 expression in these cell types.6, 7, 8 These observations suggest that two sources of IL-15 exist in HL-affected lymph nodes, which might act either in an autocrine or paracrine manner on HRS cells.

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Acknowledgements

We thank Brigitte Wollert-Wulf, Mandy Terne, Franziska Hummel, Erika Berg and Stefanie Mende for excellent technical assistance. This work was supported in part by the Deutsche Forschungsgemeinschaft (SFB-TRR54; JA 1847/1-1) and the Experimental and Clinical Research Center (Charité/MDC, Berlin).

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Authors and Affiliations

  1. Hematology, Oncology and Tumorimmunology, Max Delbrück Center for Molecular Medicine, Berlin, Germany

    K Ullrich, F Blumenthal-Barby, B Lamprecht, K Köchert, S Mathas, B Dörken & M Janz

  2. Hematology, Oncology and Tumorimmunology, Charité, University Hospital Berlin, Campus Virchow Klinikum, Berlin, Germany

    K Ullrich, F Blumenthal-Barby, B Lamprecht, K Köchert, S Mathas, B Dörken & M Janz

  3. Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany

    K Ullrich

  4. Institute of Pathology, Charité, University Hospital Berlin, Campus Benjamin Franklin, Berlin, Germany

    D Lenze & M Hummel

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Ullrich, K., Blumenthal-Barby, F., Lamprecht, B. et al. The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells. Leukemia 29, 1213–1218 (2015). https://doi.org/10.1038/leu.2014.345

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