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

Abstract

Gene expression profiles of KM-H2 cells were determined at 0, 4, 10 and 24 hours of rhIL-15 treatment and normalized to profiles of PBS-treated KM-H2 cells that were analyzed in parallel to control for expression changes induced by growth in cell culture per se. This approach identified a specific set of genes that showed a significant regulation by rhIL-15 at the respective time points, with 43 genes being differentially expressed at 24 hours (with a fold change of at least log2 0.75 ; Supplementary Table 2). To identify biological processes regulated by IL-15, we used the DAVID classification tool that classifies gene lists into functionally related gene groups. In accordance with our functional data, we observed a significant enrichment of gene ontology (GO) terms associated with cellular proliferation and survival within our set of rhIL-15-regulated genes (Supplementary Table 3). Remarkably, we 5 also found a prominent enrichment of clusters related to inflammatory processes, such as cytokine production and activity, receptor-ligand or cell-cell interactions and lymphocyte activation (Supplementary Table 3 Table 5), but are also prominent components of deregulated functional pathways in HRS cells. 14,15 As a major feature of the cellular response to IL-15 stimulation, we identified a significant induction of cytokines and chemokines in HRS cells. Several of these factors, such as IL-6, IL-9 and CCL3, in turn may have the potential to mediate growth and survival signals for HRS cells as well as to attract or stimulate cells of the tumor microenvironment. 1,2 In summary, our study identifies IL-15 as part of the complex interactions between tumor cells and the microenvironment in HL that provides growth and survival signals for HRS cells.6

Complex Immune Evasion Strategies in Classical Hodgkin Lymphoma

“…We also observed an IL15 signaling signature in cHL-Th cells (Fig. 1C) which supports the finding that HRS cells secrete IL15 (18).…”

“…are enriched in cHL-Th cells. Indeed, these factors can be expressed by HRS cells and may also be expressed by other sources in the micromilieu (17,18,30). Our analysis confirms that these factors influence gene expression in infiltrating Th cells.…”

Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma

“…IL-15 remains a surprising evasion mechanism in cHL due to its expected role in the differentiation and survival of NK cells ( 27 ). Ullrich et al found that cHL cell lines upregulate IL-15 and corresponding receptors, demonstrating that RS cells utilize IL-15 for growth and apoptosis resistance in an autocrine fashion, thereby competing with NK cells ( 68 ).…”

Effect of Roasting Levels and Drying Process of Coffea canephora on the Quality of Bioactive Compounds and Cytotoxicity

“…Experimental evidence shows that instant coffee protected lymphoma cells in animals from DNA damage and from gamma radiation in vitro [ 51 , 52 ]. In addition, the consumption of coffee may also be correlated with lower circulating levels of inflammatory markers, including chemokines, cytokines, and the basic fibroblast growth factor (FGF-2), which has been linked to lymphoma pathogenesis [ 53 , 54 ].…”