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 Waldenströ m 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.
IntroductionCytokines are protein mediators that are known to be involved in many biologic processes including cell growth, survival, inflammation, and differentiation. [1][2][3] In the malignant scenario, cytokines can profoundly affect tumor cells directly as well as the surrounding microenvironment, thereby impacting tumor cell biology. Therefore, understanding the composition of the cytokine milieu, particularly in the tumor microenvironment, is an important component of our understanding of the biology of malignant transformation. Targeting cytokines has been shown to have potent therapeutic efficacy in preclinical cancer models. 4,5 Despite the importance of cytokine networks in normal and disease states, only a limited number of studies have addressed the role of cytokines in the regulation of the tumor microenvironment in B-cell malignancies, and in particular, Waldenström macroglobulinemia (WM).WM is characterized by an infiltration of lymphoplasmacytic cells in the bone marrow accompanied by a high circulating monoclonal IgM protein that often leads to serum hyperviscosity. 6 Despite the introduction of multiple therapies, WM remains an incurable disease. Therefore, an understanding of the basic mechanisms underlying disease biology is fundamental to the development of novel therapies. In this study, we used a multiplex immunobead assay to simultaneously measure cytokines, chemokines, angiogenic factors, as well as growth factors and soluble receptors in the sera of WM patients and compared them with healthy donors. Our studies identify CCL5 (also known as regulated on activation, normal T-cell expressed, and secreted [RAN-TES]), G-CSF, and soluble IL-2 receptor ␣ (sIL-2R/CD25) as highly expressed in WM patient sera whereas IL-8 and EGF are down-regulated. Further analysis of CCL5 found that serum CCL5 levels correlated with expression of CCL5 in the bone marrow, IgM, IL-6 and bone marrow involvement by lymphoplasmacytic cells. Further analysis of the interplay between CCL5 and IL-6 indicated that CCL5 induced IL-6 secretion by WM stromal cells and identified the JAK/STAT signaling pathway as a mediator of IgM secretion in response to IL-6 stimulation. Therefore, therapies targeting CCL5 may provide therapeutic efficacy for WM patients by reducing IL-6 secretion by...