Novel Insights Into the Role of Interleukin-27 and Interleukin-23 in Human Malignant and Normal Plasma Cells

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. 2011 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 lymphocytes (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 2011 American Association for Cancer Research. (7) and B–acute lymphoblastic leukemia (ALL) cells

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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

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.

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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, respectively, and quent intramedullary and extramedullary dissemination were found to be overexpressed in different tumors. observed in multiple myeloma pathogenesis. Preclinical The proof that mir-15a was sufficient and necessary for studies showed that IL-27 downregulates MMP9, thus IL-23 antitumor activity against pediatric B-ALL cells has suggesting that IL-27 may also reduce multiple myeloma been obtained using 2 different and complementary cell invasion (Fig. 1; ref. 11). approaches. Thus, researchers have investigated whether (i) silencing of mir-15a in B-ALL cells abolished the effects Interleukin-23 driven by IL-23 and (ii) forced expression of miR15a had a IL-23 is a heterodimeric cytokine composed of the pro- similar antitumor activity to the treatment of IL-23. In vitro miscuous IL-12p40 and the exclusive p19 subunits (26). and in vivo experiments unambiguously showed that the The IL-23 receptor is composed of the IL-12 receptor b1 antileukemic function of IL-23 was strictly associated with chain and the unique IL-23 receptor chain, which is asso- the upregulation of miR-15a and that enforced expression ciated with Jak2 and STAT3 (26). In T lymphocytes and of miR-15a had antitumor activity that was similar to leukemic T cells, IL-23 induces activation of STAT family treatment with IL-23, causing a clear inhibition of leukemic members STAT1, 3, 4, and 5 (26). IL-23 is produced cell growth in vivo (4). Although the molecular mechan- predominantly by myeloid dendritic cells activated by isms underlying regulation of miR-15a mediated by IL-23 Toll-like receptor 2, 4, and 8 ligands and by type 1 macro- were not elucidated, it was hypothesized that, similar to phages (27, 28). This cytokine is now considered the other cytokines, components of the IL-23 signaling path- master switch in several T-cell–mediated inflammatory way may interfere with the biogenesis or transcription of disorders, whereas its antitumor activity remains contro- miR-15a. This preclinical study provided the first evidence versial. In this context, it has been reported that proin- that cytokine-mediated regulation of the miRNA expres- flammatory cytokines, including IL-17A, IL-6, and IL-23, sion pattern plays a key role in the control of B-ALL cell þ can impair CD8 T-lymphocyte–mediated immune sur- growth. veillance and promote de novo carcinogenesis and tumor Finally, studies on the mechanisms underlying the proa- neovascularization (29–31). In contrast, other groups have poptotic effect of IL-23 showed that the cytokine not only shown that IL-23 exerts antitumor activity through stimu- downregulated the antiapoptotic BCL-2 but also induced lation of T cells and NK cells (32–37). PARP cleavage in the absence of caspase activation (4). No information is available on IL-23 receptor expression IL-23 and Th17 function in multiple myeloma. IL-23 is a and function in normal human B cells, with the only well-known Th17-differentiating cytokine (39). Recent da- exceptions being plasma cells and early B lymphocytes ta highlighted that Th17 plays an important role in mul- (4, 5). In this context, it has been shown that human tiple myeloma pathobiology and may be an important plasma cells express complete IL-23 receptors and that therapeutic target for anti–multiple myeloma activity to IL-23 may modulate normal plasma cell functions (5). improve immune function (40). In view of these data, a However, the signal transduction activated by IL-23 treat- number of Th17-associated cytokines, including IL-23, ment has never been investigated in these cells. On the IL-21, IL-22, and IL-17, were found to be significantly contrary, it has been reported that in human normal early B elevated in multiple myeloma compared with healthy cells, IL-23 induces specific activation of the STAT3 mol- donors, and elevated IL-17 serum levels have been corre- ecule through phosphorylation of serine 727 and tyrosine lated with stage 2 and stage 3 multiple myeloma (41). In þ 701 residues, while not affecting the activation of STAT1, 4, addition, IL-23 was associated with reduced CD8 T-cell 5, and 6 (4). infiltration in the tumor microenvironment (30), and a Antitumor activity of IL-23 against myeloma and B–acute combination of Th17-associated proinflammatory cyto- lymphoblastic leukemia. Although complete IL-23 recep- kines may suppress T-cell responses. This recent evidence tor is expressed in multiple myeloma cells (I. Airoldi, suggests a potential role of IL-23 in Th17-mediated personal communication; ref. 3), IL-23 is ineffective in promotion of multiple myeloma cell growth and inhibi- terms of modulation of multiple myeloma cell proliferation tion of immune function. Finally, an imbalance between and angiogenesis, induction of apoptosis and chemotaxis, T-regulatory (Treg) and Th17, in favor of Th17, which is not

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adequately suppressed by Treg cells, may be suggested, tributes to osteoclastogenesis in an arthritis mouse model because it has been reported that Treg cells are decreased (53). In contrast, Quinn and colleagues reported that IL-23 þ in number and are dysfunctional in multiple myeloma inhibited osteoclastogenesis indirectly through CD4 patients (42). T cells and that IL-23p19 / reduced bone mass (54). Kamiya and colleagues (51) showed that IL-23 was inef- Bone remodeling in multiple myeloma fective on RANKL expression and that osteoclastogenesis Bone destruction is a hallmark of multiple myeloma induced by soluble RANKL was partially inhibited by IL-23, (43), and approximately 85% to 90% of multiple myeloma whereas proliferation of osteoclast progenitors was not patients present with lytic bone lesions frequently associ- affected. Any significant effect of IL-23 was reported on ated with severe bone pains and fractures. Osteolytic osteoblastic cells and on osteoblast formation (51). lesions result from increased bone resorption due to stim- Overall, this evidence suggests that under physiologic ulation of osteoclast formation and severely unbalanced conditions, IL-23 favors high bone mass by limiting bone bone remodeling or to decreased or absent bone formation resorption, whereas in pathophysiologic conditions, IL-23 activity that occurs close to multiple myeloma cells (44, shares a stimulatory effect on osteoclast formation, mainly 45). through the induction of RANKL by T cells and the differ- The critical role of receptor activator of NF-kB ligand entiation of Th17 subset and IL-17 production. The role (RANKL) in multiple myeloma–induced osteoclastogen- and the involvement of Th17 and IL-17 in osteoclast esis has been shown (44). RANKL is overexpressed in bone activation in multiple myeloma were recently shown marrow in relation to multiple myeloma cell infiltration, (55). Because IL-23 is a well-known cytokine involved in whereas its decoy receptor osteoprotegerin is downregu- Th17 differentiation and expansion, it is possible that the lated (44). Other cytokines produced by multiple myeloma high bone marrow levels of IL-23 observed in multiple cells, such as macrophage inhibitory protein (MIP)-1a myeloma patients (40) contribute to the increased osteo- (namely, CCL3), or induced in the microenvironment clastogenesis through the expansion of Th17 and, conse- by cell contact are responsible for enhancement of osteo- quently, the overproduction of IL-17. clast differentiation and activity and for inhibition of osteoblast functions (46). Interestingly, the growth factors Human normal plasma cells released in the course of the increased bone resorptive In humans, 3 major subsets of plasma cells have been process, as well as activated osteoclasts, in turn support isolated and are thought to represent a gradual increase in multiple myeloma cell growth and survival, thus inducing a plasma cell maturation: early plasma cells in tonsils, tran- vicious cycle (47–49). It has been consistently reported that sitional plasma cells in peripheral blood, and mature antiosteoclastic agents may exert anti–multiple myeloma plasma cells in the bone marrow (56). However, plasma effects, both in vitro and in vivo (50). cells are rare cells in vivo, representing only 1% to 2% of Effects of IL-27 and IL-23 on osteoblastic and osteoclastic tonsil mononuclear cells and less than 0.5% of bone cells and bone remodeling. Recent evidence suggests that marrow cells in healthy individuals. Thus, investigators both IL-27 and IL-23 may affect the bone remodeling developed an in vitro reproducible model of peripheral process in different ways. Osteoclast progenitors from blood B-cell differentiation into polyclonal plasmablastic multiple myeloma patients and controls (5) express func- cells (PPC), which have morphologic and phenotypic tional IL-27 receptor, and IL-27 directly decreases osteo- features of plasma cells (57). In addition, this model led clast differentiation and activity (11). It has also been to a homogenous population of normal plasmablastic cells reported that IL-27 induced proliferation in osteoblastic that provided a powerful tool for identifying genes specif- cells while not affecting osteoblast formation (11, 51), ically involved in normal plasma cell differentiation to indicating that IL-27 amplifies the mature osteoblastic further understand the biology of multiple myeloma and compartment without modulating its functionality. Thus, to improve therapeutic developments. IL-27 may counteract the unbalanced osteoclast and oste- Expression and role of IL-27 and IL-23 receptor in normal oblast activity induced by multiple myeloma cells, mainly plasma cells. The expression of both chains of IL-27 exerting an inhibitory effect on osteoclastic cells. receptor and IL-23 receptor was shown in tonsil and bone The effect of IL-23 on osteoclast and bone resorption has marrow plasma cells as well as in PPC generated in vitro, been evaluated, and results are conflicting. Yago and col- and the functional role of IL-27 and IL-23 was recently leagues (52) showed that, in human peripheral blood elucidated (5). Because production of immunoglobulin mononuclear cells, IL-23 induced osteoclastogenesis in (Ig) represents the main plasma cell function and is a the absence of exogenous soluble RANKL. In their study, key step that occurs during antigen-specific immune re- IL-17 induced by IL-23 from human-activated T cells was sponse, we asked whether IL-27 and IL-23 might modulate considered the pivotal cytokine for osteoclastogenesis Ig secretion in these cells. These experiments showed that through the involvement of the RANK–RANKL system stimulation of PPC with IL-2 in association with IL-27 or and TNF-a. Thus, IL-17 acted on monocytes and induced IL-23 caused significant upregulation of IgM secretion, osteoclast differentiation and TNF-a production by coop- paralleled by inhibition of IgG secretion and unaltered erating with RANKL. Similarly, it was reported that IL-23 IgA production. However, no effects were reported in terms þ stimulates RANKL expression on CD4 T cells and con- of modulation of IgG class switching (5, 10).

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Thus, it has been hypothesized that these cytokines are genic potential, with marginal effects on multiple myeloma effective on PPCs that have not yet undergone terminal cell proliferation and survival (3). However, a particular differentiation into antibody-secreting cells, because such note of caution about the potential therapeutic implica- effects were reverted when IL-6 was present for the last days tions of IL-12 comes from the side effects that have been of PPC culture. This latter consideration was strongly sup- reported in clinical trials addressing the antitumor activity ported by the finding that IL-23 and IL-27 had no effect on of IL-12 against different malignancies. þ modulation of Ig secretion in CD138 tonsil plasma cells. The initial clinical studies were done in phase I trials with Another novel finding was the first demonstration that patients affected by advanced malignancies (renal cancer, IL-27 possesses chemotactic properties versus plasma cells colon carcinoma, and melanoma) to determine the optimal and PPC (5), conceivably related to dependence on STAT1 treatment protocol. The parameters analyzed were toxicity, activation, as was recently shown for dendritic cells in maximum tolerated dose (MTD), biologic and antitumor response to cytokines such as IFN-b (58). activity, and route of administration. Both i.v. (61–63) and Finally, IL-27 upregulated in plasma cells and PPCs the s.c. (64, 65) injection schedules were tested in patients at expression and production of chemokines such as CXCL9, different times and doses. The IL-12 MTD differed in i.v. and which induce migration of activated T cells and NK cells s.c. routes of injection (500 ng/kg and 1,000–1,500 ng/kg, and possess potent antiangiogenic activity through IFN- respectively), and s.c. administration resulted in fewer and g–dependent and/or IFN-g–independent pathways (11, 59, milder toxic effects than i.v. treatment. Although prelimi- 60). However, in PPC and plasma cells, CXCL9–and nary studies suggested that IL-12 might be efficacious, CXCL10–modulated expression by IL-27 was not accom- subsequent trials did not confirm the first encouraging panied by induction of IFN-g production. results. Thus, despite an enhancement of immune response, Taken together, these findings support the concept that the clinical efficacy was minimal. Moreover, escalating IL-27 and, more marginally, IL-23 play an important role in doses of IL-12 induced serious side effects in patients. Good the course of immunologic response to pathogens by acting therapeutic results have been obtained in patients affected at different levels. First, IL-23 and IL-27 produced by by cutaneous T-cell lymphoma, AIDS-related Kaposi sarco- antigen-presenting cells stimulated by Toll-like receptor ma, and non-Hodgkin lymphoma that showed a clear signals may induce short-lived plasma cells to produce increase in circulating and tumor infiltrating T cells with low-affinity IgM, providing a rapid initial response to objective responses of 56%, 50%, and 43%, respectively pathogens. Thus, IL-27 may attract plasmablast and/or (66–68). The favorable results obtained in immunode- short-lived plasma cells that upregulate CXCL9, but not ficient patients with AIDS suffering from Kaposi sarcoma CCL chemokines, thus creating chemokine gradients that were not surprising because this tumor is strongly angio- recruit to inflamed tissue-activated T cells, memory T cells, genic, and angiogenesis inhibition is one of the most and NK cells but not to granulocytes and monocytes. prominent IL-12 activities. Thus, it was speculated that Finally, CXCL9 and CXCL10 may limit tissue damage the antineoplastic activity of IL-12 was largely dependent provoked by persistent activation of inflammatory cells on its ability to inhibit angiogenesis. in view of their well-known antiangiogenic activities. These To overcome or reduce systemic toxicity, novel nonviral findings may also be relevant in multiple myeloma path- delivery forms of IL-12, such as alum, liposome, and ogenesis because normal plasma cells take part in the polymer-based delivery, have shown promising effects in multiple myeloma microenvironment. Thus, the antian- preclinical models (69). A further refinement of tumor- giogenic CXCL9 upregulated in normal plasma cells may targeted IL-12 therapy would be the use of targeted for- amplify the inhibition of angiogenesis caused by the direct mulations of the cytokine, such as that developed by Halin activity of IL-27 on multiple myeloma cells. and colleagues (70), who generated a fusion protein con- taining an IL-12 moiety fused to a single-chain monoclonal Clinical–Translational Advances antibody specific for tenascin-C, an isoform of this exta- cellular matrix protein expressed predominantly in the Cytokines of the IL-12 family: potential clinical tumor stroma. This fusion protein, however, has not been implications tested in clinical trials. More recently, the effectiveness of The potential translational implication of the new evi- electrogene therapy with IL-12 has been evaluated in pre- dence on the role of IL-23 and/or IL-27 in the biology of clinical studies (71), and the antitumor efficacy was tested normal and malignant plasma cells is related to the ability in different types of primary tumors, distantly growing of these cytokines to stimulate immune responses, to tumors, and induced metastases. Intratumoral IL-12 elec- directly target tumor cells expressing the corresponding trogene therapy proved to be very effective in local tumor receptors, and, at least for IL-27, to inhibit tumor angio- control, and it also had a systemic effect; intramuscular and genesis. Either the modulation of IL-12 family cytokines, peritumoral IL-12 electrogene therapy had a pronounced including IL-23 and IL-27, or the direct use of these systemic effect. The antitumor effectiveness of IL-12 elec- cytokines, could be targeted in future clinical trials. trogene therapy was due to the induction of adaptive In the case of IL-12, preclinical studies showed that this immunity, innate resistance, and antiangiogenic action. cytokine can directly target multiple myeloma cells and A further promising area of investigation, with poten- cause a strong reduction of multiple myeloma proangio- tially relevant clinical applications, stems from the emerg-

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ing knowledge that both IL-23 and IL-27 have been used tial gene therapy through intramuscular electroporation to effectively treat tumors in murine models. Systemic (75). More recently, the efficacy of IL-27 as an antitumor administration of IL-23 has been shown to be effective agent against prostate cancer using sonoporation, a new in the mouse tumor system, including melanoma and mode of gene delivery that involves low-frequency ultra- fibrosarcoma (32, 72). In addition, preclinical evidence sound irradiation, has been reported (76). Investigators suggests that IL-23 is a promising candidate as a tumor used 3 models of immune-competent prostate adenocarci- vaccine adjuvant (37). Interestingly, adverse toxic effects of noma, and detailed characterizations of tumor growth systemic treatment with IL-23 seem to be much less than reduction, gene profile expression, and effector cellular those observed for IL-12, although some authors reported profiles were reported. Results from this investigation sug- weight loss and inflammation of the intestinal tract due to gest that IL-27 can be effective in reducing tumor growth and IL-23 schedule treatment (37). On the other hand, mice can help enhance accumulation of effector cells in prostate injected intraperitoneally with recombinant IL-23 did not tumors in vivo (76). show splenomegaly and liver inflammation compared with In conclusion, preclinical studies support the concept those treated with IL-12 (72). Therefore, from a clinical that IL-27 may represent a novel, promising therapeutic perspective, the IL-23 administration route should be agent for patients affected by different oncologic diseases, designed to avoid its adverse effects and to exert efficient potentially including multiple myeloma, based on its antitumor effect. documented multifunctional activity. Before this step, Despite the body of evidence describing the antitumoral the development of future clinical trials to evaluate the effect of IL-23 in tumoral models, caution in its clinical toxicity and efficacy of IL-27 will be mandatory. An addi- application is justified because of the role of IL-23 in tional argument in favor of this proposal is the low toxicity inflammatory diseases and its possible role in tumoral shown by IL-27 in animal models, likely in relation to the progression (30, 36, 73, 74). In fact, in mice lacking low induction of IFN-g in vivo (32). Clearly, dedicated IL-23p19 or IL-23 receptor, IL-23 showed a tumoral- studies are required to define the clinical utility of IL-27 promoting effect in contrast to its potent antitumor effect. as an antiangiogenic and antitumoral agent in patients with The reasons for this discrepancy are not known; however, solid cancer and multiple myeloma. thepotentialclinicaluseofthiscytokineshouldbe carefully evaluated. IL-23 seems to be ineffective against Disclosure of Potential Conflicts of Interest multiple myeloma cells, but its role in the control of No potential conflicts of interest were disclosed. the multiple myeloma microenvironment has not been clearly elucidated. Grant Support By contrast, we could envisage combinatorial approaches using IL-12 and IL-27 to promote T-cell and NK-cell This work was supported by grants from A.I.R.C., Milan, Italy (numbers 4014 responses against multiple myeloma, in addition to their to I. Airoldi and 8530 to N. Giuliani), Italian Ministry of Health (RF, RC, 5/1000, Progetto Strategico Oncologico 2006 rif070701), International Myeloma Foun- direct antitumor activity against multiple myeloma and the dation (to N. Giuliani), Italian Ministry of Health-Progetti Regione Emilia ability of IL-27 to stimulate osteoblast proliferation and Romagna, and the Special Program Molecular Clinical Oncology 5 per mille inhibit osteoclast differentiation and function. In light of (number 9965). this activity, exciting results have been reported against Received July 5, 2011; revised August 3, 2011; accepted August 10, 2011; melanoma and breast cancer using IL-12 and IL-27 sequen- published OnlineFirst August 31, 2011.

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6970 Clin Cancer Res; 17(22) November 15, 2011 Clinical Cancer Research

Novel Insights into the Role of Interleukin-27 and Interleukin-23 in Human Malignant and Normal Plasma Cells

Nicola Giuliani and Irma Airoldi

Clin Cancer Res 2011;17:6963-6970. Published OnlineFirst August 31, 2011.

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