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Myeloid derived suppressor cells and their role in tolerance induction in cancer
Journal of Dermatological Science 59 (2010) 1–6
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Journal of Dermatological Science journal homepage: www.elsevier.com/jds
Invited review article
Myeloid derived suppressor cells and their role in tolerance induction in cancer Taku Fujimura *, Karsten Mahnke, Alexander H. Enk Department of Dermatology, University Hospital Heidelberg, Voss strasse 11, 69115, Heidelberg, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 April 2010 Received in revised form 11 May 2010 Accepted 13 May 2010
Myeloid derived suppressor cells (MDSCs) comprise a phenotypically heterogeneous population of cells, which can be found in tumor-bearing mice and in patients with cancer. MDSCs play a central role in the induction of peripheral tolerance. Together with regulatory T cells (Tregs) they promote an immunosuppressive environment in tumor-bearing hosts. The phenotype of MDSCs differs in humans and mice, and the exact mechanisms of their suppressive function are still controversially discussed. In summary, MDSCs are a group of phenotypically heterogeneous cells of myeloid origin that have common biological activities. In this review, we discuss the definition of MDSCs, the proposed mechanisms of expansion and the recruitment and activation of MDSCs, as well as their biological activities in tumorbearing hosts to assess the potential therapeutic applications. ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: MDSC Tumorimmunology Cancer
Contents 1. 2. 3.
4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The definition of MDSCs . . . . . . . . . . . . . . . . . . . Expansion and recruitment of MDSCs . . . . . . . . 3.1. Tumor-associated inflammation. . . . . . . . 3.2. Angiogenic factors. . . . . . . . . . . . . . . . . . . 3.3. Chemoattractant factors . . . . . . . . . . . . . . Mechanisms of suppressive activities of MDSCs MDSC as a therapeutic target . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Several clinical trials for cancer immunotherapy reveal that cancer vaccination therapies can strengthen the immune system against tumors, but their clinical benefits to induce complete tumor regression are still limited [1,2]. This discrepancy is, at least in part, due to immunosuppressive cells in the tumor microenvironment. Myeloid derived suppressor cells (MDSCs) are one of the key suppressor cells that regulate anti-tumor immune responses in conjunction with regulatory T cells (Tregs) in tumor-bearing hosts. MDSCs were originally described as a population of CD11b+Gr1+ cells that accumulate in blood and lymphoid organs of tumor-
* Corresponding author. Tel.: +49 6221 568170; fax: +49 6221 561617. E-mail address: [email protected] (T. Fujimura).
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1 2 3 3 3 3 3 4 5 5 5
bearing mice [3,4]. Currently, MDSCs have been reported to comprise a group of heterogeneous immature myeloid cells, which have suppressive biological activities as a common denominator. MDSCs regulate both acquired and innate immunity by direct or indirect pathways. To exert their immunosuppressive function in tumor-bearing hosts, MDSCs are (i) required to expand in lymphoid organs and (ii) are subsequently recruited to the tumor site [3,5]. There are several factors (e.g. tumor-associated inflammation, angiogenetic factors, chemoattractant fantoes) that orchestrate the expansion and recruitment of MDSCs. This expansion of MDSC is associated with a poor prognosis in tumor-bearing hosts. The activation of MDSCs in tumors upregulates the expression of inducible nitric oxide synthase (iNOS), arginase 1 (ARG 1), and increases the production of nitric oxide (NO) and reactive oxygen species (ROS). Moreover, classical immunosuppressive cytokines such as IL-10 or TGF-b are also
0923-1811/$36.00 ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2010.05.001
T. Fujimura et al. / Journal of Dermatological Science 59 (2010) 1–6
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Fig. 1. MDSCs are heterogenous population of immature myeloid cells both human and mouse. MDSCs suppress acquired and innate anti-tumor immunity through several different mechanisms.
secreted. By these means, MDSCs suppress the anti-tumor immune response in the tumor microenvironment directly. Moreover, not only direct effects on effector immune cells are apparent, as MDSCs are involved in the induction of Tregs. These results clearly suggest that the suppression of MDSC-inducible factors or Tregs, respectively, may be beneficial for anti-cancer therapy. In this review, we discuss the definition and suppressive mechanisms of MDSCs, as well as their biological activities in tumor-bearing hosts to assess potential therapeutic strategies (Fig. 1, Table 1). 2. The definition of MDSCs MDSCs comprise a phenotypically heterogeneous population of cells, which can be found in tumor-bearing mice and in patients with cancer. In mice, MDSCs were originally described as a population of CD11b+ Gr1+ cells that accumulate in the blood and lymphoid organs during tumor growth [3,4]. The Gr1 antigen includes the macrophage and neutrophil marker Ly6C and Ly6G, whereas CD11b is characteristic for macrophages. Movahedi et al. divided MDSCs into CD11b+Ly6G+ and CD11b+Ly6C+ subpopulations and reported that the concise mechanism of immunosuppression is different in these two subsets [6]. Suppressive effects of
Table 1 Manipulation of MDSCs functions. Substance
Mechanism
Effect
Ref
Cox2 inhibitors
Arginase I #
[19,20]
PDE5 inhibitors
IL-4Ra # Arginase 1 # Inos # Tregs # ROS
Anti-tumor T cell response " Anti-tumor T cell response "
Anti-tumor T cell response " Differentiation of MDSC " Total number of MDSC #
[48,49]
All-trans retinoic acid
Gemcitabine
Amino-bisphosphonate
Directly killing MDSCs MMP9 #
Recruitment of MDSC #
[43]
[46]
[28]
CD11b+Ly6G+ are mediated by IFN-g, while those of CD11b+Ly6C+ are mediated by nitric oxide (NO). CD115 (M-CSF receptor) and CD124 (IL-4Ra) are also described as being a marker for subsets of MDSCs [7–9]. CD11b+CD115+ directly suppress antigen-stimulated splenocytes through NO production, whereas CD11b+CD124+ MDSCs, but not CD11b+CD124 cells, suppress the generation of alloreactive CTLs through IL-13 and IFN-g in murine colon carcinoma models [7,8]. For murine MDSCs even more molecules have been described. For example, retinoic acid early inducible-1 gene (RAE-1), which is known as the mouse NK-cell activating receptor NKG2D, is expressed on CD11b+Gr1+F4/80+ MDSCs isolated from murine lymphoma bearing mice [10]. Likewise, the triggering receptor expressed on myeloid cells 1 (TREM-1) is also upregulated on CD11b+Gr1+F4/80+ MDSCs [11]. Thus, these markers suggest a phenotypic heterogeneity of MDSCs and underline the importance of assessing functional activities for the separation of MDSCs from conventional macrophages. In humans, MDSCs are even less well defined and there are no specific markers known yet. For instance, human cells do not express a marker homologous to mouse Gr1. Instead of being Gr1+, the phenotype of MDSCs in humans is defined as CD11b+CD14CD33+, or Lin HLA-DR CD33+ [12,13]. Similar to murine models, several reports suggest CD124 as a marker for MDSCs [14] and Mandruzzato et al. proposed that the upregulation of CD124 in mononuclear cells, but not polymorphonuclear granulocytes, correlates with the immunosuppressive function of MDSCs in patients with colon cancer or malignant melanoma [14]. More recently, CD66b, a member of the carcinoembryonic antigen (CEA)-like glycoprotein family present on granulocytes, is reported to serve as a marker for a subpopulation of CD11b+CD14CD33+CD66b+ MDSCs in patients with renal cell carcinoma [15]. These cells possess clearly enhanced suppressive capacity as compared to CD66b MDSCs. As MDSCs are a group of phenotypically heterogeneous cells that have only immunosuppressive activities in common, additional markers, such as CD66b are appreciated for specifying the phenotypes better. Because there are no common markers for human MDSCs in different types of tumors, further investigations are required to assess the function of MDSC-subtypes during tumor growth and to correlate it with the prognosis of cancer patients.
T. Fujimura et al. / Journal of Dermatological Science 59 (2010) 1–6
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3. Expansion and recruitment of MDSCs
3.2. Angiogenic factors
To assess the immunosuppressive function of MDSCs in tumor models, it is important to investigate their systemic expansion, recruitment to the tumor site and enhancement of the suppressive function. In this section, we discuss the expansion and recruitment of MDSCs that is related to tumor-associated inflammation, angiogenic factors and other chemoattractants.
Previous reports indicated that the vascular endothelial growth factor (VEGF) released by tumors is one of the main factors responsible for expansion of CD11b+Gr1+ immature myeloid cells by inhibition of DC maturation [24,25]. This effect seems partly to be mediated by MMP-9, as this protease remodels the extracellular matrix and consequently promotes the growth of new blood vessels by stimulating the production of VEGF. Indeed, Yang et al. reported the requirement of matrix metalloproteinase-9 (MMP-9) for expansion and maintenance of MDSCs [26]. Furthermore, in murine mammary carcinoma models, tumor resident CD11b+Gr1+ MDSCs facilitate tumor cell invasion and metastasis through MMP activity by inducing TGFb1 in the tumors [27]. More recently, pharmacological inhibition of MMP-9 by amino-biphosphonate, which decreases pro-MMP-9 and VEGF in the serum, is reported to abrogate the induction of MDSCs [28]. Thus these reports clearly indicate the contribution of CD11b+Gr1+ MDSC derived MMPs to tumor invasion and metastasis.
3.1. Tumor-associated inflammation Previously, proinflammatory cytokines, such as IL-1b, IL-6 and bioactive lipid PGE2 were reported to induce the accumulation of MDSCs, which supports the notion that tumor-associated inflammation is of importance to expand MDSCs in tumorbearing hosts. Tumor-derived IL-1b expands Gr1+CD11b+ immature myeloid cells in the spleen, which facilitates tumor growth and survival [16]. Other results indicate that this tumor-derived IL-1b does not directly activate MDSC. Instead IL-1b is believed to trigger an inflammatory cascade, which as a consequence induces the MDSCs by release of other cytokines in tumor-bearing host [17]. As a possible candidate IL-6 is discussed. IL-6 is a cytokines located downstream of IL-1b in inflammatory responses, and Bunt et al. demonstrated that the induction of MDSCs is partially restored by IL-6 in IL-1b deficient mice [18]. This report clearly suggests that inflammation is able to induce MDSCs by activation via IL-1b/IL-6 pathways in tumor-bearing hosts and to facilitate tumor growth. In addition to cytokines, bioactive lipids, such as prostagrandin E2 (PGE2) and cyclooxygenase 2 (COX2) are produced by many tumors and are known as major contributors to the inflammatory tumor milieu. Effects of these substances on MDSC are also apparent, as Rodriguez et al. previously demonstrated that PGE2 and COX-2 amplify arginase 1 levels in MDSCs. Moreover, genetic or pharmacologic inhibition of COX-2 blocked the expression of arginase 1 and induced an anti-tumor immune response [19]. Sinha et al. also reported that the tumor-derived PGE2 and/or COX-2 significantly induce MDSCs from bone marrow precursor cells through the EP2/4 receptor. Along these lines it has also been demonstrated that treatment of tumorbearing mice with COX-2 inhibitors reduced the frequency of MDSCs in tumors and blood and slowed down tumor growth [20]. In aggregate these reports suggest an interrelation between expansion of MDSCs and inflammation, mediated by the arachidonic acid cascade. More recently, S100A8/A9, which are known as calciumbinding proteins released by neutrophils, are reported to be able to induce MDSCs. Cheng et al. demonstrated that S100A9 blocks the differentiation of myeloid precursors into functional dendritic cells or macrophages through a STAT3-dependent pathway [21]. They report that mice lacking this protein exhibit reduced MDSC numbers and rejected transplanted EL-4 lymphoma spontaneously. Sinha et al. also reported that S100A8/A9 complexes contribute to the recruitment of MDSCs to tumor sites through NF-kB dependent pathways [22]. Moreover, the role of S100A8/A9 proteins is of particular interest, as MDSCs produce S100A8/A9 proteins by themselves, suggesting that S100A8/A9 proteins provide an autocrine feedback loop to accumulate MDSCs at tumor sites. Finally, even the complement system seems to be involved in governing the activity of MDSCs, as it has been reported that C5a enhances the expression of ROS and reactive nitrogen species through C5a receptor on MDSCs in cervical tumorbearing mice [23]. This report clearly indicates that complement factors induce MDSCs and thus facilitates the tumor growth in vivo.
3.3. Chemoattractant factors Chemokines are important factors involved in shaping the tumor microenvironment. Several reports suggested that CCL2 (MCP-1)/CCR2 is necessary to attract MDSCs into the tumor microenvironment [29]. Sawanobori et al. further demonstrated that CCR2 attracted MDSCs are mainly macrophage-like MDSCs (CD11b+Gr-1int/dulLy-6Chi), which directly interfere with tumor growth [29]. At the same time the authors also reported that the lack of CCR2 in mice caused an attraction of neutrophil-like MDSCs (CD11b+Gr-1hiLy-6Cint) to the tumor site. Thus CCR2 may shape the tumor infiltrating MDSC towards a macrophage -like, tumor promoting phenotype. In another report, Pan et al. demonstrate that tumor-derived stem cell factor (SCF) leads to myelopoiesis and the expansion of MDSCs by inhibiting differentiation of myeloid precursor to functional dendritic cells [30]. Thus, these data may implicate that in the absence of other DC-differentiating factors, the default pathway of some myeloid precursors may be the development of MDSC subpopulations. SDF-1/CXCR4 and CXCL5/CXCR2 contribute to the recruitment of MDSCs to the tumor site, at least in a murine mammary carcinoma model [27]. But in contrast to SCF, these chemokines specifically recruit already fully developed MDSCs and do not interfere with their differentiation from precursors to mature MDSCs. Finally, urokinase plasminogen activator (uPA), which is known to induce tumor progression, also correlates with the recruitment of MDSCs in murine mammary carcinoma models [31,32]. These results are supported by findings of Hanson et al., demonstrating that intraperitoneal injection of uPA significantly elevated the numbers of MDSCs in spleens. Thus, these results suggest that the tumor progressing effect of uPA may at least in part be mediated by MDSCs. Although these mechanisms are not completely understood yet, it would be an attractive aim to devise novel anti-cancer therapies by targeting these MDSCs-inducing pathways with specific drugs. 4. Mechanisms of suppressive activities of MDSCs To exert their suppressive activity, MDSCs must be activated. Indeed, there are several factors reported, which stimulate MDSCs to turn their suppressive function on. IL-4, IL-13, IFN-g, IL-1b and TGF-b are known to activate several different pathways in MDSCs that involve STAT6, STAT1 and nuclear factor-kB (NF-kB). STAT1, STAT3 and STAT6 have been described to have distinct roles in macrophage polarization [4]. While STAT3 regulates the
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T. Fujimura et al. / Journal of Dermatological Science 59 (2010) 1–6
expansion of MDSCs through the S100A9/N-glycan pathway [21] and the accumulation of reactive oxygen species (ROS) [33], STAT6 and STAT1 regulate the activation of MDSCs to express arginase 1 and iNOS [3,34, 35]. IL-4 and IL-13 were reported to activate STAT6 signaling through the IL-4Ra pathway [35], while IL-1b and IFN-g activate the STAT1 signaling cascade [34]. In addition to induce arginase 1 and iNOS, the IL-4Ra/STAT6 pathway also elicits the production of TGF-b by MDSCs [36]. Current reports also suggested that IFN-g is required for activation of the MDSCs by induction of STAT1 signaling [6,34]. It was shown that inhibition of IFN-g, which is derived from activated T cells, NK-cells and MDSCs themselves, abrogates the suppressive function of the MDSCs by downregulation of iNOS and arginase 1 expression [6,10,34]. Part of the suppressive function of MDSCs is mediated by the metabolism of L-arginine. It has been suggested that MDSCs express high levels of arginase 1 and iNOS, both of which inhibit T cell proliferation [3,4,37]. Arginase 1 enhances the L-arginine catabolism, which causes a shortage of L-arginine in the tumor microenvironment and inhibits T cell proliferation by decreasing their expression of the CD3-z chains [38] and by induction of a cell cycle arrest of proliferating T cells in the G0–G1 phase [39]. Moreover, NO, which has been shown to be produced by MDSC, suppresses T cell proliferation by inhibiting expression of MHC class II [40] and induction of T cell apoptosis [37]. These antiproliferative effects are mainly mediated by inhibition of JAK3 and STAT5 functions in the target cells. [37,41]. The production of radical oxygen species (ROS) also contributes to the suppressive activity of MDSCs in both tumor-bearing mice and cancer patients, as increased ROS levels in MDSCs induce the upregulation of several subunits of the NADPH oxidase. This inhibits MDSC maturation through STAT3 signaling pathways [33]. Further effects of MDSCs-derived ROS include (i) induction of DNA damage in immune cells resident in the tumor microenvironment, (ii) inhibition of the differentiation of MDSCs into functional DCs and (iii) recruitment of MDSCs to the tumor site [3]. Moreover, extracellular ROS catalyzes the nitration of the TCR, which consequently inhibits the T cell-peptide-MHC interaction resulting in T cell suppression [42]. Not only direct suppressive effects of MDSC in the tumor microenvironment have been described. MDSCs can also act indirectly, for instance by the induction of regulatory T cells (Tregs) in the tumor microenvironment. In a murine colon carcinoma model, Gr1+CD115+ MDSCs induce the development of Tregs from adoptively transferred antigen specific CD25CD4+ T cells in the presence of IL-10 and IFN-g [8]. In another report, MDSCs are reported as tolerogenic antigen presenting cells, which present tumor-specific antigens to Tregs and expand tumor-specific Tregs by arginase dependent and TGF-b independent pathways [43]. Yang et al. further demonstrated that suppressive functions of Gr1+CD11b+ MDSC were supported by CD4+CD25+ Tregs. In a mouse ovarian tumor model, Gr1+CD11b+ MDSCs express CD80, which maintains elevated numbers of Tregs in peripheral lymphoid organs by engaging with CD152 expressed by Tregs. After blockage or deletion of CD80 on MDSC, the suppressive function of Treg was significantly downregulated. Thus, the cellular interaction of MDSC and Treg via the CD80/CD152 pathway may contribute to tumor tolerance, at least in mouse ovarian tumor models [44]. MDSCs not only actively promote the recruitment of Tregs to tumor sites, but at the same time also block the entry of effector T cells to the tumor. For instance, MDSCs abrogate the expression of + + L-selectin on both CD4 and CD8 T cells, suppressing the homing of these cells to the tumor site where they would be activated [32]. As a consequence the balance between immunosuppressive cells and anti-tumor effector T cells is further tilted towards a dominant immunosuppressive microenvironment.
5. MDSC as a therapeutic target After expansion in the periphery, MDSCs migrate to tumor sites and become activated to express arginase 1 and iNOS. Indeed, the levels of NO and arginase 1 in tumor sites are much higher as compared to the periphery [4]. Moreover, these activated MDSCs produce immunosuppressive cytokines such as IL-10 and TGF-b to promote a systemic immunosuppression against tumors [45]. MDSCs even secrete IFN-g. Instead of being directly immunosuppressive, IFN-g enhances the production of TGF-b and IL-10 by MDSCs. Accumulating reports describe the relationship between the number of MDSCs and the survival rate of tumor-bearing hosts [3,4]. In essence these data clearly demonstrate a direct correlation of elevated MDSC numbers in the tumor with an unfavorable prognosis of survival. Although the statistical basis in these investigations is relatively small, the results suggest that MDSCs play a central role in induction of peripheral tolerance. Thus, depletion of the cells or abrogation of their suppressive function may be a promising tool to support anti-cancer therapies in the future The enzyme COX2 is involved in guiding the production of critical enzymes in MDSCs. The application of COX2 inhibitors is able to reduce the expression of arginase-1 in MDSCs, resulting in the improvement of anti-tumor T cell responses and enhancing the effectiveness of anti-tumor immunotherapies [19]. Similar to COX2 inhibitors, phosphoesterase 5 (PDE5) inhibition reverses the tumor-immunosuppressive mechanism of MDSCs by downregulation of the expression of the IL-4Ra, arginase 1 and iNOS by MDSCs. Moreover, this treatment even reduces the induction of Tregs. Collectively these murine data suggest that the deactivation of functions of MDSCs by PDE5 inhibitors significantly slows down tumor growth [43]. The deletion of MDSCs can further support anti-cancer therapies to break tolerance in tumor-bearing hosts [3,46]. In murine models, it has been shown that the chemotherapeutic drug gemcitabine was able to specifically reduce the number of CD11b+Gr1+ MDSCs in the spleen. On the contrary, in human models, one report suggested that the administration of antitumor drugs to breast cancer patients significantly increased the number of circulating LinHLA-DRCD33 +CD11b+ MDSCs in all tumor stages [47]. This discrepancy is, at least in part, caused by the heterogeneities of MDSCs especially in humans and supports the need for the concise functional analysis of MDSCs. Especially in clinical applications further investigations will be required to connect the phenotypic analysis and functional analysis of MDSCs. As mentioned previously, the targeting of MDSC-inducing factors may also provide a promising tool for anti-cancer therapy. In this regard MMP9 may serve as a suitable target. MMP9 induces expansion and recruitment of MDSCs to tumor sites and is mainly produced in the tumor microenvironment by tumor stromal cells of bone marrow origin. The tissue concentration of MMP9 increases with tumor progression and even upregulates VEGF in the serum, which causes the further induction of MDSCs in tumors. Thus, tumor-residing MDSCs maintain their population by recruiting further MDSCs to the tumor by producing MMP9. The drug Amino-bisphosphonate which is known to ameliorate osteoporosis, has been reported to inhibit the production of MMP9 by tumor stromal cells, preventing the recruitment of MDSCs [28]. This evidence clearly indicates that this reagent breaks the positive feedback loop of MDSC maintenance in tumors by interfering with the recruitment of MDSCs to tumor sites. Because MDSCs represent a group of cells of myeloid lineage at different stages of differentiation, induction of differentiation into a less harmful phenotype of MDSCs is another therapeutic approach to avoid immune suppression of anti-tumor responses by MDSCs. All-trans retinoic acid induces the differentiation of
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MDSCs into functional DC or macrophages [48]. The mechanism of all-trans retinoic acid-mediated anti-immunosuppressive effects may be twofold: At first the administration of all-trans retinoic acid results in differentiation of MDSCs from several cancer patients into functional DC [49], which then can contribute to an augmentation of anti–cancer immune responses by stimulating effector T cells; And secondly, all-trans retinoic acid reduces ROS levels in MDSCs, which significantly reduces the recruitment of MDSCs to tumor sites [48]. In summary, all-trans retinoic acid can be an adjuvant reagent for cancer patients, to attenuate the immunosuppressive effects created by MDSCs. 6. Concluding remarks MDSCs are a group of heterogeneous immature myeloid cells that have common biological activities, i.e. the suppression of immune responses. Although several studies suggested that high numbers of MDSCs in tumor-bearing individuals is associated with poor prognosis, further investigations will be required to quantify the impact of MSDC on survival in different cancers. Clinical studies for targeting MDSCs are limited to only a few tumor types (e.g. renal cell carcinoma, colon caner, melanoma) and the expanding phenotypes of MDSCs (e.g. granulocytic cells, monocytic cells, polymorphonuclear cells) are difficult to discriminate in tumors of different origin. In this aspect, MDSCs must be more clearly characterized to make them suitable as a clinical target. Because the abrogation of the MDSC function in tumor-bearing mice has been shown to amplify anti-tumor immune responses, targeting of MDSCs may be an optimal supportive therapy for cancer immunotherapies in humans. Acknowledgement This study was supported by Alexander von Humboldt foundation, the Tumor center Heidelberg/Mannheim and the Helmholtz Alliance against Cancer. References [1] Finn OJ. Cancer immunology. N Engl J Med 2008;358:2704–15. [2] Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004;10:909–15. [3] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162–74. [4] Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 2007;117:1155–66. [5] Ostrand-Rosenberg S, Sinha P. Myeloid derived suppressor cells: linking inflammation and cancer. J Immunol 2009;182:4499–506. [6] Movahedi K, Guilliams M, Van den Bossche J, Van Den Bergh R, Gysemans C, Beschin A, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulation with distinct T cell-suppressive activity. Blood 2008;111:4233–44. [7] Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo MP, et al. Tumor induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 2006;116:2777–90. [8] Huang B, Pan PY, LI Q, Sato AI, Lew DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell energy in tumor-bearing host. Cancer Res 2006;66:1123–31. [9] Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid derived suppressor cells in tumor-bearing mice. J Immunol 2008;181:5791–802. [10] Nausch N, Galani I, Schlecker E, Cerwenka A. Mononuclear myeloid-derived ‘‘suppressor’’ cells express RAE-1 and activate natural killer cells. Blood 2008;112:4080–9. [11] Zanzinger K, Schellack C, Nausch N, Cerwenka A. Regulation of triggering receptor expressed on myeloid cell 1 expression on mouse inflammatory monocytes. Immunology 2009;128:185–95. [12] Zea A, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, et al. Arginase-producing myeloid derived suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 2005;65:3044–8. [13] Kusmartsev S, Su Z, Heiser A, Dannull J, Eruslanov E, Kuebler H, et al. Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res 2008;14:8270–8.
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[23] Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C, et al. Modulation of the antitumor immune response by complement. Nat Immunol 2008;9:1225–35. [24] Melani C, Chiodoni C, Forni G, Colombo MP. Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 2003;102:2138–45. [25] Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affect the differentiation of multiple hematopoietic linages in vivo. Blood 1998;92:4150–66. [26] Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, et al. Expansion of myeloid immune suppressive Gr1+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004;6:409–21. [27] Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, et al. Abrogation of TGFb singaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 2008;13:23–35. [28] Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res 2007;67:11438–46. [29] Sawanobori Y, Ueha S, Kurachi M, Shimaoka T, Talmadge JE, Abe J, et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 2008;111:5457–66. [30] Pan PY, Wang GX, Yin B, Ozao J, Ku T, Divino CM, et al. Reversion of immunotolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem cell factor function. Blood 2008;111:219–28. [31] Ilkovitch D, Lopez DM. Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC/sec. Blood 2009;113:4729–39. [32] Hanson EM, Clement VK, Sinha P, Ilkovitch D, Ostrand-Rosenberg S. Myeloidderived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J Immunol 2009;183:937–44. [33] Corzo C, Cotter MJ, Cheng P, Cheng F, Kusmartsev S, Sotomayor E, et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid derived suppressor cells. J Immunol 2009;182:5693–701. [34] Kusmartsev S, Gabrilovich DI. STAT1 signaling regulates tuomr-associated macrophage-mediated T cell deletion. J Immunol 2005;174:4880–91. [35] Rutschman R, Lang R, Hesse M, Ihle JN, Wynn TA, Murray PJ. Cutting edge: Stat6-dependent substrate depletion regulate nitric oxide production. J Immunol 2001;166:2173–7. [36] Terabe M, Matsui S, Park JM, Mamura M, Noben-Trauth N, Donaldson DD, et al. Transforming growth factor-b production and myeloid cells are an effector mechanism through which CD1d-restricted T cell block cytotoxic T lympocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 2003;198:1741–52. [37] Bronte V, Serafini P, Mazzoni A, Segal DM, Zanovello P. L-arginine metabolism in myeloid cell controls T-lymphocyte functions. Trend Immunol 2003;24: 302–6. [38] Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC. Regulation of T cell receptor CD3z chain expression by L-arginine. J Biol Chem 2002;277: 21123–9. [39] Rodriguez PC, Quiceno DG, Ochoa AC. L-arginine availability reglates T-lymphocyte cell-cycle progression. Blood 2007;109:1568–73. [40] Kielar ML, Sicher SC, Penfield JG, Jeyarajah DR, Lu CY. Nitric oxide inhibits INF gamma-induced increases in CIITA mRNA abundance and activation of CIITA dependent genes—class II MHC, Il and H-2 M. Class II trans activator. Inflammation 2000;24:431–45.
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Dr. Taku Fujimura graduated from Tohoku University, graduate school of medicine and received his MD degree in 1998. He received his PhD in dermatology at Tohoku University in 2004. From 2004 to 2007, he worked as an assistant professor in Department of Dermatology, Tohoku University graduate school of medicine. Since 2007, he has studied tumor immunology under the supervision of Professor Alexander H Enk and Professor Karsten Mahnke at Department of Dermatology, University of Heidelberg as a Humbolt Foundation fellow where he investigated the crosstalk of myeloid derived suppressor cells and regulatory T cells during melanoma growth. His research interests include tumor immunology and cutaneous immunology.
Contents lists available at ScienceDirect
Journal of Dermatological Science journal homepage: www.elsevier.com/jds
Invited review article
Myeloid derived suppressor cells and their role in tolerance induction in cancer Taku Fujimura *, Karsten Mahnke, Alexander H. Enk Department of Dermatology, University Hospital Heidelberg, Voss strasse 11, 69115, Heidelberg, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 April 2010 Received in revised form 11 May 2010 Accepted 13 May 2010
Myeloid derived suppressor cells (MDSCs) comprise a phenotypically heterogeneous population of cells, which can be found in tumor-bearing mice and in patients with cancer. MDSCs play a central role in the induction of peripheral tolerance. Together with regulatory T cells (Tregs) they promote an immunosuppressive environment in tumor-bearing hosts. The phenotype of MDSCs differs in humans and mice, and the exact mechanisms of their suppressive function are still controversially discussed. In summary, MDSCs are a group of phenotypically heterogeneous cells of myeloid origin that have common biological activities. In this review, we discuss the definition of MDSCs, the proposed mechanisms of expansion and the recruitment and activation of MDSCs, as well as their biological activities in tumorbearing hosts to assess the potential therapeutic applications. ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: MDSC Tumorimmunology Cancer
Contents 1. 2. 3.
4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The definition of MDSCs . . . . . . . . . . . . . . . . . . . Expansion and recruitment of MDSCs . . . . . . . . 3.1. Tumor-associated inflammation. . . . . . . . 3.2. Angiogenic factors. . . . . . . . . . . . . . . . . . . 3.3. Chemoattractant factors . . . . . . . . . . . . . . Mechanisms of suppressive activities of MDSCs MDSC as a therapeutic target . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Several clinical trials for cancer immunotherapy reveal that cancer vaccination therapies can strengthen the immune system against tumors, but their clinical benefits to induce complete tumor regression are still limited [1,2]. This discrepancy is, at least in part, due to immunosuppressive cells in the tumor microenvironment. Myeloid derived suppressor cells (MDSCs) are one of the key suppressor cells that regulate anti-tumor immune responses in conjunction with regulatory T cells (Tregs) in tumor-bearing hosts. MDSCs were originally described as a population of CD11b+Gr1+ cells that accumulate in blood and lymphoid organs of tumor-
* Corresponding author. Tel.: +49 6221 568170; fax: +49 6221 561617. E-mail address: [email protected] (T. Fujimura).
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bearing mice [3,4]. Currently, MDSCs have been reported to comprise a group of heterogeneous immature myeloid cells, which have suppressive biological activities as a common denominator. MDSCs regulate both acquired and innate immunity by direct or indirect pathways. To exert their immunosuppressive function in tumor-bearing hosts, MDSCs are (i) required to expand in lymphoid organs and (ii) are subsequently recruited to the tumor site [3,5]. There are several factors (e.g. tumor-associated inflammation, angiogenetic factors, chemoattractant fantoes) that orchestrate the expansion and recruitment of MDSCs. This expansion of MDSC is associated with a poor prognosis in tumor-bearing hosts. The activation of MDSCs in tumors upregulates the expression of inducible nitric oxide synthase (iNOS), arginase 1 (ARG 1), and increases the production of nitric oxide (NO) and reactive oxygen species (ROS). Moreover, classical immunosuppressive cytokines such as IL-10 or TGF-b are also
0923-1811/$36.00 ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2010.05.001
T. Fujimura et al. / Journal of Dermatological Science 59 (2010) 1–6
2
Fig. 1. MDSCs are heterogenous population of immature myeloid cells both human and mouse. MDSCs suppress acquired and innate anti-tumor immunity through several different mechanisms.
secreted. By these means, MDSCs suppress the anti-tumor immune response in the tumor microenvironment directly. Moreover, not only direct effects on effector immune cells are apparent, as MDSCs are involved in the induction of Tregs. These results clearly suggest that the suppression of MDSC-inducible factors or Tregs, respectively, may be beneficial for anti-cancer therapy. In this review, we discuss the definition and suppressive mechanisms of MDSCs, as well as their biological activities in tumor-bearing hosts to assess potential therapeutic strategies (Fig. 1, Table 1). 2. The definition of MDSCs MDSCs comprise a phenotypically heterogeneous population of cells, which can be found in tumor-bearing mice and in patients with cancer. In mice, MDSCs were originally described as a population of CD11b+ Gr1+ cells that accumulate in the blood and lymphoid organs during tumor growth [3,4]. The Gr1 antigen includes the macrophage and neutrophil marker Ly6C and Ly6G, whereas CD11b is characteristic for macrophages. Movahedi et al. divided MDSCs into CD11b+Ly6G+ and CD11b+Ly6C+ subpopulations and reported that the concise mechanism of immunosuppression is different in these two subsets [6]. Suppressive effects of
Table 1 Manipulation of MDSCs functions. Substance
Mechanism
Effect
Ref
Cox2 inhibitors
Arginase I #
[19,20]
PDE5 inhibitors
IL-4Ra # Arginase 1 # Inos # Tregs # ROS
Anti-tumor T cell response " Anti-tumor T cell response "
Anti-tumor T cell response " Differentiation of MDSC " Total number of MDSC #
[48,49]
All-trans retinoic acid
Gemcitabine
Amino-bisphosphonate
Directly killing MDSCs MMP9 #
Recruitment of MDSC #
[43]
[46]
[28]
CD11b+Ly6G+ are mediated by IFN-g, while those of CD11b+Ly6C+ are mediated by nitric oxide (NO). CD115 (M-CSF receptor) and CD124 (IL-4Ra) are also described as being a marker for subsets of MDSCs [7–9]. CD11b+CD115+ directly suppress antigen-stimulated splenocytes through NO production, whereas CD11b+CD124+ MDSCs, but not CD11b+CD124 cells, suppress the generation of alloreactive CTLs through IL-13 and IFN-g in murine colon carcinoma models [7,8]. For murine MDSCs even more molecules have been described. For example, retinoic acid early inducible-1 gene (RAE-1), which is known as the mouse NK-cell activating receptor NKG2D, is expressed on CD11b+Gr1+F4/80+ MDSCs isolated from murine lymphoma bearing mice [10]. Likewise, the triggering receptor expressed on myeloid cells 1 (TREM-1) is also upregulated on CD11b+Gr1+F4/80+ MDSCs [11]. Thus, these markers suggest a phenotypic heterogeneity of MDSCs and underline the importance of assessing functional activities for the separation of MDSCs from conventional macrophages. In humans, MDSCs are even less well defined and there are no specific markers known yet. For instance, human cells do not express a marker homologous to mouse Gr1. Instead of being Gr1+, the phenotype of MDSCs in humans is defined as CD11b+CD14CD33+, or Lin HLA-DR CD33+ [12,13]. Similar to murine models, several reports suggest CD124 as a marker for MDSCs [14] and Mandruzzato et al. proposed that the upregulation of CD124 in mononuclear cells, but not polymorphonuclear granulocytes, correlates with the immunosuppressive function of MDSCs in patients with colon cancer or malignant melanoma [14]. More recently, CD66b, a member of the carcinoembryonic antigen (CEA)-like glycoprotein family present on granulocytes, is reported to serve as a marker for a subpopulation of CD11b+CD14CD33+CD66b+ MDSCs in patients with renal cell carcinoma [15]. These cells possess clearly enhanced suppressive capacity as compared to CD66b MDSCs. As MDSCs are a group of phenotypically heterogeneous cells that have only immunosuppressive activities in common, additional markers, such as CD66b are appreciated for specifying the phenotypes better. Because there are no common markers for human MDSCs in different types of tumors, further investigations are required to assess the function of MDSC-subtypes during tumor growth and to correlate it with the prognosis of cancer patients.
T. Fujimura et al. / Journal of Dermatological Science 59 (2010) 1–6
3
3. Expansion and recruitment of MDSCs
3.2. Angiogenic factors
To assess the immunosuppressive function of MDSCs in tumor models, it is important to investigate their systemic expansion, recruitment to the tumor site and enhancement of the suppressive function. In this section, we discuss the expansion and recruitment of MDSCs that is related to tumor-associated inflammation, angiogenic factors and other chemoattractants.
Previous reports indicated that the vascular endothelial growth factor (VEGF) released by tumors is one of the main factors responsible for expansion of CD11b+Gr1+ immature myeloid cells by inhibition of DC maturation [24,25]. This effect seems partly to be mediated by MMP-9, as this protease remodels the extracellular matrix and consequently promotes the growth of new blood vessels by stimulating the production of VEGF. Indeed, Yang et al. reported the requirement of matrix metalloproteinase-9 (MMP-9) for expansion and maintenance of MDSCs [26]. Furthermore, in murine mammary carcinoma models, tumor resident CD11b+Gr1+ MDSCs facilitate tumor cell invasion and metastasis through MMP activity by inducing TGFb1 in the tumors [27]. More recently, pharmacological inhibition of MMP-9 by amino-biphosphonate, which decreases pro-MMP-9 and VEGF in the serum, is reported to abrogate the induction of MDSCs [28]. Thus these reports clearly indicate the contribution of CD11b+Gr1+ MDSC derived MMPs to tumor invasion and metastasis.
3.1. Tumor-associated inflammation Previously, proinflammatory cytokines, such as IL-1b, IL-6 and bioactive lipid PGE2 were reported to induce the accumulation of MDSCs, which supports the notion that tumor-associated inflammation is of importance to expand MDSCs in tumorbearing hosts. Tumor-derived IL-1b expands Gr1+CD11b+ immature myeloid cells in the spleen, which facilitates tumor growth and survival [16]. Other results indicate that this tumor-derived IL-1b does not directly activate MDSC. Instead IL-1b is believed to trigger an inflammatory cascade, which as a consequence induces the MDSCs by release of other cytokines in tumor-bearing host [17]. As a possible candidate IL-6 is discussed. IL-6 is a cytokines located downstream of IL-1b in inflammatory responses, and Bunt et al. demonstrated that the induction of MDSCs is partially restored by IL-6 in IL-1b deficient mice [18]. This report clearly suggests that inflammation is able to induce MDSCs by activation via IL-1b/IL-6 pathways in tumor-bearing hosts and to facilitate tumor growth. In addition to cytokines, bioactive lipids, such as prostagrandin E2 (PGE2) and cyclooxygenase 2 (COX2) are produced by many tumors and are known as major contributors to the inflammatory tumor milieu. Effects of these substances on MDSC are also apparent, as Rodriguez et al. previously demonstrated that PGE2 and COX-2 amplify arginase 1 levels in MDSCs. Moreover, genetic or pharmacologic inhibition of COX-2 blocked the expression of arginase 1 and induced an anti-tumor immune response [19]. Sinha et al. also reported that the tumor-derived PGE2 and/or COX-2 significantly induce MDSCs from bone marrow precursor cells through the EP2/4 receptor. Along these lines it has also been demonstrated that treatment of tumorbearing mice with COX-2 inhibitors reduced the frequency of MDSCs in tumors and blood and slowed down tumor growth [20]. In aggregate these reports suggest an interrelation between expansion of MDSCs and inflammation, mediated by the arachidonic acid cascade. More recently, S100A8/A9, which are known as calciumbinding proteins released by neutrophils, are reported to be able to induce MDSCs. Cheng et al. demonstrated that S100A9 blocks the differentiation of myeloid precursors into functional dendritic cells or macrophages through a STAT3-dependent pathway [21]. They report that mice lacking this protein exhibit reduced MDSC numbers and rejected transplanted EL-4 lymphoma spontaneously. Sinha et al. also reported that S100A8/A9 complexes contribute to the recruitment of MDSCs to tumor sites through NF-kB dependent pathways [22]. Moreover, the role of S100A8/A9 proteins is of particular interest, as MDSCs produce S100A8/A9 proteins by themselves, suggesting that S100A8/A9 proteins provide an autocrine feedback loop to accumulate MDSCs at tumor sites. Finally, even the complement system seems to be involved in governing the activity of MDSCs, as it has been reported that C5a enhances the expression of ROS and reactive nitrogen species through C5a receptor on MDSCs in cervical tumorbearing mice [23]. This report clearly indicates that complement factors induce MDSCs and thus facilitates the tumor growth in vivo.
3.3. Chemoattractant factors Chemokines are important factors involved in shaping the tumor microenvironment. Several reports suggested that CCL2 (MCP-1)/CCR2 is necessary to attract MDSCs into the tumor microenvironment [29]. Sawanobori et al. further demonstrated that CCR2 attracted MDSCs are mainly macrophage-like MDSCs (CD11b+Gr-1int/dulLy-6Chi), which directly interfere with tumor growth [29]. At the same time the authors also reported that the lack of CCR2 in mice caused an attraction of neutrophil-like MDSCs (CD11b+Gr-1hiLy-6Cint) to the tumor site. Thus CCR2 may shape the tumor infiltrating MDSC towards a macrophage -like, tumor promoting phenotype. In another report, Pan et al. demonstrate that tumor-derived stem cell factor (SCF) leads to myelopoiesis and the expansion of MDSCs by inhibiting differentiation of myeloid precursor to functional dendritic cells [30]. Thus, these data may implicate that in the absence of other DC-differentiating factors, the default pathway of some myeloid precursors may be the development of MDSC subpopulations. SDF-1/CXCR4 and CXCL5/CXCR2 contribute to the recruitment of MDSCs to the tumor site, at least in a murine mammary carcinoma model [27]. But in contrast to SCF, these chemokines specifically recruit already fully developed MDSCs and do not interfere with their differentiation from precursors to mature MDSCs. Finally, urokinase plasminogen activator (uPA), which is known to induce tumor progression, also correlates with the recruitment of MDSCs in murine mammary carcinoma models [31,32]. These results are supported by findings of Hanson et al., demonstrating that intraperitoneal injection of uPA significantly elevated the numbers of MDSCs in spleens. Thus, these results suggest that the tumor progressing effect of uPA may at least in part be mediated by MDSCs. Although these mechanisms are not completely understood yet, it would be an attractive aim to devise novel anti-cancer therapies by targeting these MDSCs-inducing pathways with specific drugs. 4. Mechanisms of suppressive activities of MDSCs To exert their suppressive activity, MDSCs must be activated. Indeed, there are several factors reported, which stimulate MDSCs to turn their suppressive function on. IL-4, IL-13, IFN-g, IL-1b and TGF-b are known to activate several different pathways in MDSCs that involve STAT6, STAT1 and nuclear factor-kB (NF-kB). STAT1, STAT3 and STAT6 have been described to have distinct roles in macrophage polarization [4]. While STAT3 regulates the
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expansion of MDSCs through the S100A9/N-glycan pathway [21] and the accumulation of reactive oxygen species (ROS) [33], STAT6 and STAT1 regulate the activation of MDSCs to express arginase 1 and iNOS [3,34, 35]. IL-4 and IL-13 were reported to activate STAT6 signaling through the IL-4Ra pathway [35], while IL-1b and IFN-g activate the STAT1 signaling cascade [34]. In addition to induce arginase 1 and iNOS, the IL-4Ra/STAT6 pathway also elicits the production of TGF-b by MDSCs [36]. Current reports also suggested that IFN-g is required for activation of the MDSCs by induction of STAT1 signaling [6,34]. It was shown that inhibition of IFN-g, which is derived from activated T cells, NK-cells and MDSCs themselves, abrogates the suppressive function of the MDSCs by downregulation of iNOS and arginase 1 expression [6,10,34]. Part of the suppressive function of MDSCs is mediated by the metabolism of L-arginine. It has been suggested that MDSCs express high levels of arginase 1 and iNOS, both of which inhibit T cell proliferation [3,4,37]. Arginase 1 enhances the L-arginine catabolism, which causes a shortage of L-arginine in the tumor microenvironment and inhibits T cell proliferation by decreasing their expression of the CD3-z chains [38] and by induction of a cell cycle arrest of proliferating T cells in the G0–G1 phase [39]. Moreover, NO, which has been shown to be produced by MDSC, suppresses T cell proliferation by inhibiting expression of MHC class II [40] and induction of T cell apoptosis [37]. These antiproliferative effects are mainly mediated by inhibition of JAK3 and STAT5 functions in the target cells. [37,41]. The production of radical oxygen species (ROS) also contributes to the suppressive activity of MDSCs in both tumor-bearing mice and cancer patients, as increased ROS levels in MDSCs induce the upregulation of several subunits of the NADPH oxidase. This inhibits MDSC maturation through STAT3 signaling pathways [33]. Further effects of MDSCs-derived ROS include (i) induction of DNA damage in immune cells resident in the tumor microenvironment, (ii) inhibition of the differentiation of MDSCs into functional DCs and (iii) recruitment of MDSCs to the tumor site [3]. Moreover, extracellular ROS catalyzes the nitration of the TCR, which consequently inhibits the T cell-peptide-MHC interaction resulting in T cell suppression [42]. Not only direct suppressive effects of MDSC in the tumor microenvironment have been described. MDSCs can also act indirectly, for instance by the induction of regulatory T cells (Tregs) in the tumor microenvironment. In a murine colon carcinoma model, Gr1+CD115+ MDSCs induce the development of Tregs from adoptively transferred antigen specific CD25CD4+ T cells in the presence of IL-10 and IFN-g [8]. In another report, MDSCs are reported as tolerogenic antigen presenting cells, which present tumor-specific antigens to Tregs and expand tumor-specific Tregs by arginase dependent and TGF-b independent pathways [43]. Yang et al. further demonstrated that suppressive functions of Gr1+CD11b+ MDSC were supported by CD4+CD25+ Tregs. In a mouse ovarian tumor model, Gr1+CD11b+ MDSCs express CD80, which maintains elevated numbers of Tregs in peripheral lymphoid organs by engaging with CD152 expressed by Tregs. After blockage or deletion of CD80 on MDSC, the suppressive function of Treg was significantly downregulated. Thus, the cellular interaction of MDSC and Treg via the CD80/CD152 pathway may contribute to tumor tolerance, at least in mouse ovarian tumor models [44]. MDSCs not only actively promote the recruitment of Tregs to tumor sites, but at the same time also block the entry of effector T cells to the tumor. For instance, MDSCs abrogate the expression of + + L-selectin on both CD4 and CD8 T cells, suppressing the homing of these cells to the tumor site where they would be activated [32]. As a consequence the balance between immunosuppressive cells and anti-tumor effector T cells is further tilted towards a dominant immunosuppressive microenvironment.
5. MDSC as a therapeutic target After expansion in the periphery, MDSCs migrate to tumor sites and become activated to express arginase 1 and iNOS. Indeed, the levels of NO and arginase 1 in tumor sites are much higher as compared to the periphery [4]. Moreover, these activated MDSCs produce immunosuppressive cytokines such as IL-10 and TGF-b to promote a systemic immunosuppression against tumors [45]. MDSCs even secrete IFN-g. Instead of being directly immunosuppressive, IFN-g enhances the production of TGF-b and IL-10 by MDSCs. Accumulating reports describe the relationship between the number of MDSCs and the survival rate of tumor-bearing hosts [3,4]. In essence these data clearly demonstrate a direct correlation of elevated MDSC numbers in the tumor with an unfavorable prognosis of survival. Although the statistical basis in these investigations is relatively small, the results suggest that MDSCs play a central role in induction of peripheral tolerance. Thus, depletion of the cells or abrogation of their suppressive function may be a promising tool to support anti-cancer therapies in the future The enzyme COX2 is involved in guiding the production of critical enzymes in MDSCs. The application of COX2 inhibitors is able to reduce the expression of arginase-1 in MDSCs, resulting in the improvement of anti-tumor T cell responses and enhancing the effectiveness of anti-tumor immunotherapies [19]. Similar to COX2 inhibitors, phosphoesterase 5 (PDE5) inhibition reverses the tumor-immunosuppressive mechanism of MDSCs by downregulation of the expression of the IL-4Ra, arginase 1 and iNOS by MDSCs. Moreover, this treatment even reduces the induction of Tregs. Collectively these murine data suggest that the deactivation of functions of MDSCs by PDE5 inhibitors significantly slows down tumor growth [43]. The deletion of MDSCs can further support anti-cancer therapies to break tolerance in tumor-bearing hosts [3,46]. In murine models, it has been shown that the chemotherapeutic drug gemcitabine was able to specifically reduce the number of CD11b+Gr1+ MDSCs in the spleen. On the contrary, in human models, one report suggested that the administration of antitumor drugs to breast cancer patients significantly increased the number of circulating LinHLA-DRCD33 +CD11b+ MDSCs in all tumor stages [47]. This discrepancy is, at least in part, caused by the heterogeneities of MDSCs especially in humans and supports the need for the concise functional analysis of MDSCs. Especially in clinical applications further investigations will be required to connect the phenotypic analysis and functional analysis of MDSCs. As mentioned previously, the targeting of MDSC-inducing factors may also provide a promising tool for anti-cancer therapy. In this regard MMP9 may serve as a suitable target. MMP9 induces expansion and recruitment of MDSCs to tumor sites and is mainly produced in the tumor microenvironment by tumor stromal cells of bone marrow origin. The tissue concentration of MMP9 increases with tumor progression and even upregulates VEGF in the serum, which causes the further induction of MDSCs in tumors. Thus, tumor-residing MDSCs maintain their population by recruiting further MDSCs to the tumor by producing MMP9. The drug Amino-bisphosphonate which is known to ameliorate osteoporosis, has been reported to inhibit the production of MMP9 by tumor stromal cells, preventing the recruitment of MDSCs [28]. This evidence clearly indicates that this reagent breaks the positive feedback loop of MDSC maintenance in tumors by interfering with the recruitment of MDSCs to tumor sites. Because MDSCs represent a group of cells of myeloid lineage at different stages of differentiation, induction of differentiation into a less harmful phenotype of MDSCs is another therapeutic approach to avoid immune suppression of anti-tumor responses by MDSCs. All-trans retinoic acid induces the differentiation of
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MDSCs into functional DC or macrophages [48]. The mechanism of all-trans retinoic acid-mediated anti-immunosuppressive effects may be twofold: At first the administration of all-trans retinoic acid results in differentiation of MDSCs from several cancer patients into functional DC [49], which then can contribute to an augmentation of anti–cancer immune responses by stimulating effector T cells; And secondly, all-trans retinoic acid reduces ROS levels in MDSCs, which significantly reduces the recruitment of MDSCs to tumor sites [48]. In summary, all-trans retinoic acid can be an adjuvant reagent for cancer patients, to attenuate the immunosuppressive effects created by MDSCs. 6. Concluding remarks MDSCs are a group of heterogeneous immature myeloid cells that have common biological activities, i.e. the suppression of immune responses. Although several studies suggested that high numbers of MDSCs in tumor-bearing individuals is associated with poor prognosis, further investigations will be required to quantify the impact of MSDC on survival in different cancers. Clinical studies for targeting MDSCs are limited to only a few tumor types (e.g. renal cell carcinoma, colon caner, melanoma) and the expanding phenotypes of MDSCs (e.g. granulocytic cells, monocytic cells, polymorphonuclear cells) are difficult to discriminate in tumors of different origin. In this aspect, MDSCs must be more clearly characterized to make them suitable as a clinical target. Because the abrogation of the MDSC function in tumor-bearing mice has been shown to amplify anti-tumor immune responses, targeting of MDSCs may be an optimal supportive therapy for cancer immunotherapies in humans. Acknowledgement This study was supported by Alexander von Humboldt foundation, the Tumor center Heidelberg/Mannheim and the Helmholtz Alliance against Cancer. References [1] Finn OJ. Cancer immunology. N Engl J Med 2008;358:2704–15. [2] Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004;10:909–15. [3] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162–74. [4] Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 2007;117:1155–66. [5] Ostrand-Rosenberg S, Sinha P. Myeloid derived suppressor cells: linking inflammation and cancer. J Immunol 2009;182:4499–506. [6] Movahedi K, Guilliams M, Van den Bossche J, Van Den Bergh R, Gysemans C, Beschin A, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulation with distinct T cell-suppressive activity. Blood 2008;111:4233–44. [7] Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo MP, et al. Tumor induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 2006;116:2777–90. [8] Huang B, Pan PY, LI Q, Sato AI, Lew DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell energy in tumor-bearing host. Cancer Res 2006;66:1123–31. [9] Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid derived suppressor cells in tumor-bearing mice. J Immunol 2008;181:5791–802. [10] Nausch N, Galani I, Schlecker E, Cerwenka A. Mononuclear myeloid-derived ‘‘suppressor’’ cells express RAE-1 and activate natural killer cells. Blood 2008;112:4080–9. [11] Zanzinger K, Schellack C, Nausch N, Cerwenka A. Regulation of triggering receptor expressed on myeloid cell 1 expression on mouse inflammatory monocytes. Immunology 2009;128:185–95. [12] Zea A, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, et al. Arginase-producing myeloid derived suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 2005;65:3044–8. [13] Kusmartsev S, Su Z, Heiser A, Dannull J, Eruslanov E, Kuebler H, et al. Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res 2008;14:8270–8.
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Dr. Taku Fujimura graduated from Tohoku University, graduate school of medicine and received his MD degree in 1998. He received his PhD in dermatology at Tohoku University in 2004. From 2004 to 2007, he worked as an assistant professor in Department of Dermatology, Tohoku University graduate school of medicine. Since 2007, he has studied tumor immunology under the supervision of Professor Alexander H Enk and Professor Karsten Mahnke at Department of Dermatology, University of Heidelberg as a Humbolt Foundation fellow where he investigated the crosstalk of myeloid derived suppressor cells and regulatory T cells during melanoma growth. His research interests include tumor immunology and cutaneous immunology.