title: Comprehensive analysis of tumor microenvironment cytokines in Waldenstrom macroglobulinemia identifies CCL5 as a novel modulator of IL-6 activity.
abstract: Although proinflammatory and chemotactic cytokines can profoundly affect the tumor microenvironment, and many of them have been shown to have therapeutic efficacy in preclinical models, the role of these molecules in Waldenström macroglobulinemia (WM) remains poorly understood. In this study, simultaneous analysis of WM patient sera and bone marrow biopsies identified a set of dysregulated cytokines including CCL5, G-CSF, and soluble IL-2 receptor, that were significantly elevated in WM patients whereas IL-8 and EGF levels were significantly lower in these patients compared with healthy controls. Interestingly, CCL5 levels positively correlated with features of disease aggressiveness such as elevated IgM levels and bone marrow involvement. Functional analysis of tumor microenvironment revealed a functional correlation between CCL5 levels and IL-6 levels, a proinflammatory cytokine with an important role in normal and malignant B-cell biology. Furthermore, CCL5 stimulated IL-6 secretion in WM stromal cells resulting in increased IgM secretion by WM malignant cells via the JAK/STAT signaling pathway. Thus, together these results define a novel signaling network in the WM tumor microenvironment controlling IgM secretion and suggest CCL5 as a potential target for the treatment of this disease.
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Sherine F
authors.initials: SF
authors.lastname: Elsawa
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ziesmer
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.forename: Lucy S
authors.initials: LS
authors.lastname: Hodge
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Grote
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
mesh_terms: D001706:Biopsy; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D018946:Chemokine CCL5 / Q000097:blood / Q000276:immunology*; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology*; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*; D008258:Waldenstrom Macroglobulinemia / Q000276:immunology* / Q000473:pathology / Q000628:therapy
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; C508600:IL6 protein, human; D007075:Immunoglobulin M; D015850:Interleukin-6; D019707:Receptors, Chemokine