Published OnlineFirst August 31, 2011; DOI: 10.1158/1078-0432.CCR-11-1724 Clinical Cancer Molecular Pathways Research Novel Insights into the Role of Interleukin-27 and Interleukin-23 in Human Malignant and Normal Plasma Cells Nicola Giuliani1 and Irma Airoldi2 Abstract Multiple myeloma is a monoclonal postgerminal center tumor that has phenotypic features of plasmablasts and/or plasma cells and usually localizes at multiple sites in the bone marrow. The pathogenesis of multiple myeloma is complex and dependent on the interactions between tumor cells and their microenvironment. Different cytokines, chemokines, and proangiogenic factors released in the tumor microenvironment are known to promote multiple myeloma cell growth. Here, we report recent advances on the role of 2 strictly related immunomodulatory cytokines, interleukin-27 (IL-27) and IL-23, in human normal and neoplastic plasma cells, highlighting their ability to (i) act directly against multiple myeloma cells, (ii) influence the multiple myeloma microenvironment by targeting osteoclast and osteoblast cells, and (iii) modulate normal plasma cell function. Finally, the therapeutic implication of these studies is discussed. Clin Cancer Res; 17(22); 6963–70. Ó2011 AACR. Background resulting in enhancement the of na€ve cluster of differen- þ tiation (CD)4 T-cell proliferation, promotion of the early Interleukin (IL)-27 and IL-23 are immunomodulatory T-helper (Th)1 differentiation, and suppression of the cytokines that belong to the IL-12 superfamily (1), which differentiation of Th2 and Th17 cells. In addition, IL-27 comprises structurally and functionally related heterodi- plays a key role in generating IL-10–producing regulatory meric cytokines, including IL-12, IL-23, IL-27, and IL-35 T cells (1, 9). (1). These cytokines are predominantly produced by anti- In human tonsils, the different B-cell subsets show gen-presenting cells in response to microbial or host im- variable expression of IL-27 receptor (10). Investigators mune stimuli and are involved in the regulation of immune have found that na€ve and memory B lymphocytes consti- responses against infections and tumor development (2). tutively expressed both chains of IL-27 receptor, whereas Recent preclinical studies showed the direct antitumor germinal center B cells exhibited only barely detectable activities of IL-12 family cytokines in different human levels of the WSX-1 chain. However, the WSX-1 was found hematologic malignancies, including pediatric acute leu- to be strongly upregulated during germinal center to mem- kemias and multiple myeloma, as well as in solid tumors ory B-cell transition (10). In terms of signal transduction, (3–7). Here, we report and discuss recent advances in the IL-27 induces a strong phosphorylation of both STAT1 and role of IL-27 and IL-23 in multiple myeloma cells and their STAT3 in na€ve B cells, whereas moderate STAT1 and low microenvironment and in human normal plasma cells. activation of STAT3 were observed in memory B lympho- cytes (10). In addition, human plasma cells constitutively Interleukin-27 express WSX-1 and gp130, and IL-27 specifically induces IL-27 is composed of the EBI3 and p35 subunits and STAT1 phosphorylation while not affecting STAT3 or activates both STAT1 and STAT3 through a distinct IL-27 STAT5 activation (5). Differences in the STAT activation receptor, which consists of the unique receptor subunit driven by IL-27 may reflect the different ability of human B- WSX-1 paired with the gp130 chain (8). In T lymphocytes, cell subsets to respond to IL-27. For example, IL-27 the cytokine induces STAT1 and STAT3 activation, thus enhances proliferation in na€ve and activated germinal center B cells (10); induces surface expression of CD54, CD95, and CD86 in stimulated memory B cells (10); and Authors' Affiliations: 1Hematology and Blood and Marrow Transplanta- tion (BMT) Center, University of Parma, Parma, Italy; 2Associazione Italiana exerts chemotactic activity on plasma cells (5). Ricerca sul Cancro (A.I.R.C.) Laboratory of Immunology and Tumors, Antitumor activity of IL-27 against myeloma cells. IL-27, Department of Experimental and Laboratory Medicine, G. Gaslini Institute, similar to IL-12, shows antitumor activity in different Genoa, Italy cancers through indirect mechanisms, such as induction Corresponding Author: Irma Airoldi, A.I.R.C. Laboratory of Immunology and Tumors, Department of Experimental and Laboratory Medicine, of natural killer (NK) and CTL response or inhibition of G. Gaslini Institute, 16148 Genoa, Italy. Phone: 39-0105636342; Fax: angiogenesis, primarily due to induction of CXCL10 and 39-010377982; E-mail: [email protected] CXCL9 (3, 11–14). In addition, it has been reported that doi: 10.1158/1078-0432.CCR-11-1724 IL-27 directly inhibits the growth of melanoma cell lines Ó2011 American Association for Cancer Research. (7) and B–acute lymphoblastic leukemia (ALL) cells www.aacrjournals.org 6963 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst August 31, 2011; DOI: 10.1158/1078-0432.CCR-11-1724 Giuliani and Airoldi expressing complete IL-27 receptor (12). In multiple my- involved and are under investigation. We reported that eloma, it has been reported that both chains of IL-27 IL-27 downregulates in vitro a wide panel of proangiogenic þ receptor are expressed in CD138 multiple myeloma cells molecules, including VEGF-A, VEGF-C, and VEGF-D, from patients (5, 11). Although IL-27 does not modulate angiopoietins, and matrix metalloproteinases (MMP), multiple myeloma cell proliferation and apoptosis, a and it upregulates the antiangiogenic chemokines CXCL9 strong reduction of the angiogenic potential of multiple and CXCL10 (Fig. 1; ref. 11). Accordingly, preclinical myeloma cells was clearly documented (5). It is of note that studies using highly immunodeficient nonobese diabet- bone marrow neovascularization contributes to the biolo- ic/severe combined immunodeficient mice injected with gy of several hematologic malignancies (15), and multiple multiple myeloma cells revealed that IL-27 inhibits mul- myeloma neoangiogenesis may be induced by angiogenic tiple myeloma cell growth through inhibition of angiogen- cytokines produced by tumor and microenvironmental esis, which caused ischemic necrosis in the tumors. In this cells (16). Cytokines, such as basic fibroblast growth factor, model, the main proangiogenic molecules and multiple VEGF, and angiopoietins, play a leading role in new vessel myeloma growth factors downregulated by IL-27 were IL-6, formation as well as in tumor angiogenesis (17–19). How- VEGF-D, and CCL2, which also serve as autocrine and/or ever, other known and unknown factors may also be paracrine growth factors (20, 21). Thus, we can envisage CXCL9 CXCL10 VEGF-A Angiogenesis VEGF-C IL-27 VEGF-D TGF-β Angiopoietins IL-27 IL-27 MMP2 MMP9 Invasiveness IL-1β TNF Activated MM cells bone marrow stromal cells MMP1 MMP2 IL-1β IL-27 TNF VEGF-A VEGF-C VEGF-D IL-6 © 2011 American Association for Cancer Research Figure 1. IL-27 activity against multiple myeloma (MM) cells and the paracrine growth loop. IL-27 directly acts on multiple myeloma cells that express complete IL-27 receptor. IL-27 inhibits the angiogenic potential of multiple myeloma cells and downregulates different angiogenic factors that also serve as autocrine and/or paracrine growth factors. IL-27 may interrupt or reduce the growth loop in which cytokines and growth factors released by multiple myeloma cells induce paracrine stimulation of stromal cells, which, in turn, secrete additional growth factors that stimulate new vessel formation and support multiple myeloma cell proliferation, progression, and migration. 6964 Clin Cancer Res; 17(22) November 15, 2011 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst August 31, 2011; DOI: 10.1158/1078-0432.CCR-11-1724 IL-23 and IL-27 in Multiple Myeloma that IL-27 may interrupt or reduce the growth loop (Fig. 1), regulation of chemokine receptor expression, and cytokine in which cytokines and growth factors released by multiple production. The mechanisms underlying the lack of func- myeloma cells induce paracrine stimulation of stromal tion of IL-23 receptor in these cells remain to be established. cells, which, in turn, secrete additional growth factors, such A different scenario has been envisaged using IL-23 as a as IL-6 and VEGF, which induce new vessel formation and potential antitumor agent against pediatric B-ALL (4). In support multiple myeloma cell proliferation, progression, this context, it has been shown that IL-23 reduces B-ALL cell and migration. In addition, multiple myeloma cells and growth in vitro and in preclinical models by inhibiting bone marrow stromal cells produce MMPs that degrade proliferation and inducing apoptosis. Such effects were collagens and fibronectin, thus rendering multiple myelo- related to IL-23–induced upregulation of miR-15a in leu- ma cells capable of invading both stroma and the sub- kemic cells and to the consequent downregulation of the endothelial basement membrane (Fig. 1; refs. 22–25). The target proteins BCL-2 and cyclin D1 (38). These 2 mole- enhanced invasive ability of multiple myeloma cells and cules function as oncogenes, play an important role in the their increased angiogenic capacity may explain the fre- regulation of apoptosis and proliferation,