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T Cells Favoring Tumor Growth CCR5-Dependent Recruitment Of Tumor-Infiltrating Monocytic Myeloid-Derived Suppressor Cells Mediate CCR5-Dependent Recruitment of Regulatory T Cells Favoring Tumor Growth This information is current as of September 27, 2021. Eva Schlecker, Ana Stojanovic, Christian Eisen, Christian Quack, Christine S. Falk, Viktor Umansky and Adelheid Cerwenka J Immunol 2012; 189:5602-5611; Prepublished online 14 November 2012; Downloaded from doi: 10.4049/jimmunol.1201018 http://www.jimmunol.org/content/189/12/5602 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2012/11/14/jimmunol.120101 Material 8.DC1 References This article cites 49 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/189/12/5602.full#ref-list-1 Why The JI? Submit online. by guest on September 27, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Tumor-Infiltrating Monocytic Myeloid-Derived Suppressor Cells Mediate CCR5-Dependent Recruitment of Regulatory T Cells Favoring Tumor Growth Eva Schlecker,* Ana Stojanovic,* Christian Eisen,† Christian Quack,‡ Christine S. Falk,‡ Viktor Umansky,x,{ and Adelheid Cerwenka* Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells in cancer patients and tumor- bearing mice that potently inhibits T cell responses. During tumor progression, MDSCs accumulate in several organs, including the tumor tissue. So far, tumor-infiltrating MDSC subpopulations remain poorly explored. In this study, we performed global gene expression profiling of mouse tumor-infiltrating granulocytic and monocytic (MO-MDSC) subsets compared with MDSCs from peripheral blood. RMA-S lymphoma–infiltrating MO-MDSCs not only produced high levels of NO and arginase-1, but also Downloaded from greatly increased levels of chemokines comprising the CCR5 ligands CCL3, CCL4, and CCL5. MO-MDSCs isolated from B16 melanoma and from skin tumor–bearing ret transgenic mice also expressed high levels of CCL3, CCL4, and CCL5. Expression of CCR5 was preferentially detected on regulatory T cells (Tregs). Accordingly, tumor-infiltrating MO-MDSCs directly attracted high numbers of Tregs via CCR5 in vitro. Intratumoral injection of CCL4 or CCL5 increased tumor-infiltrating Tregs, and deficiency of CCR5 led to their profound decrease. Moreover, in CCR5-deficient mice, RMA-S and B16 tumor growth was delayed emphasizing the importance of CCR5 in the control of antitumor immune responses. Overall, our data demonstrate that chemo- http://www.jimmunol.org/ kines secreted by tumor-infiltrating MO-MDSCs recruit high numbers of Tregs revealing a novel suppressive role of MDSCs with potential clinical implications for the development of cancer immunotherapies. The Journal of Immunology, 2012, 189: 5602–5611. ultiple mechanisms of immune suppression accompa- 7). Several mechanisms for their direct suppressive activity on nying tumor development have been reported (1). T cells were reported, such as the production of reactive oxygen M Alterations in myelopoiesis that occur during tumor species (ROS) and nitrogen species and arginase-1 (8) or by de- growth lead to the accumulation of myeloid-derived suppressor priving cysteine from the environment (9). So far, most studies cells (MDSCs). MDSCs represent a heterogeneous population of investigated the accumulation, subset distribution, and regulatory myeloid cells at different stages of differentiation (2, 3). In mice, role of MDSCs in bone marrow, blood, and spleen. Comparatively by guest on September 27, 2021 MDSCs are characterized by the coexpression of the cell-surface little is known about their function within the tumor tissue of solid markers Gr-1 and CD11b. Within this population, two MDSC malignancies including lymphoma and melanoma. subsets with distinct morphological features have been identified Regulatory T cells (Tregs) represent another suppressive pop- comprising monocytic MDSCs (MO-MDSCs) that express high ulation that potently inhibits T cell and NK cell function in cancer levels of Ly6C and F4/80 and granulocytic MDSCs (PMN- patients and tumor-bearing mice (10–12). CD4+CD25+ Tregs ex- MDSCs) expressing Ly6G and no F4/80 (4, 5). MDSCs potently pressing the transcription factor Foxp3 inhibit autoimmune re- inhibit T cell proliferation and cytokine production in vitro (3, 6, sponses and promote tumor progression (13, 14). Accordingly, the depletion of Tregs results in improved antitumor immune responses and delays tumor growth in many tumor models (15). High numbers *Innate Immunity, Research Program Tumor Immunology, German Cancer Research ofTregsintumorssuchaslymphoma(16)areoftenassociatedwith Center, Heidelberg D-69120, Germany; †Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg D-69120, Germany; ‡Immune Monitoring Unit, poor prognosis for cancer patients. Several mechanisms of Treg National Center for Tumor Diseases, German Cancer Research Center, Heidelberg D- recruitment to tumors were reported. In breast and prostate cancer 69120, Germany; xSkin Cancer Unit, German Cancer Research Center, Heidelberg D- { patients, CCL22 present in the tumor microenvironment mediated 69120, Germany; and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Treg trafficking in a CCR4-dependent manner (17, 18). Recently, it Mannheim, Heidelberg 68167, Germany was shown that tumor-derived CCL28 mediates CCR10-dependent Received for publication April 5, 2012. Accepted for publication October 3, 2012. Treg recruitment in ovarian cancer (19). In a mouse model of This work was supported by the Deutsche Krebshilfe (109174 to A.C.). pancreatic adenocarcinoma that produces CCL5, increased Treg The sequences presented in this article have been submitted to Gene Expression numbers were associated with CCR5 expression by Tregs (20). Omnibus under accession number GSE41620 (http://www.ncbi.nlm.nih.gov/geo/ However, whether additional cells, like tumor-infiltrating immune query/acc.cgi?acc=GSE41620). cells, mediate CCR5-dependent Treg recruitment remains elusive. Address correspondence and reprint requests to Dr. Adelheid Cerwenka, German Recent evidence demonstrates that MDSCs and Tregs interact Cancer Research Center, DKFZ/D080, Im Neuenheimer Feld 280, D-69120 Heidel- berg, Germany. E-mail address: [email protected] with each other to build a suppressive network during antitumor The online version of this article contains supplemental material. immune responses. In this context, it was shown that CD40 (21), Abbreviations used in this article: iNOS, inducible NO synthase; KO, knockout; CD80 (22), and arginase-1 expression (23) by MDSCs are in- MDSC, myeloid-derived suppressor cell; MO-MDSC, monocytic myeloid-derived volved in the induction of Treg development and T cell tolerance suppressor cell; PMN-MDSC, granulocytic myeloid-derived suppressor cell; ROS, in spleen, bone marrow, and ascites. It has been recently reported reactive oxygen species; Treg, regulatory T cell; wt, wild-type. that CCL5 gene expression in blood-derived MDSCs was down- Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 regulated by treatments with tolerating regimen affecting the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1201018 The Journal of Immunology 5603 intragraft localization of Tregs (24). Whether tumor-infiltrating Chemotaxis assay MDSCs interact with Tregs within the tumor tissue of solid Tregs from spleens of naive C57BL/6-CD45.1+ mice or CCR52/2 mice tumors and influence each other’s accumulation and recruitment were enriched by magnetic beads using CD4+CD25+ isolation kit (Miltenyi remains to be investigated. Biotec; purity $95%) and stimulated with 5 mg/ml anti-CD3/CD28 mAbs In our study, we performed global gene arrays of tumor-infiltrating overnight in serum-free primary cell medium (RPMI with 1% L-glutamine, MDSC subsets to gain insight in their function within the tumor 1% penicillin, 1% streptomycin, 1% nonessential amino acids, 1% sodium pyruvate, and 50 mM 2-ME). This preactivation increased the percentages tissue. Our data demonstrate that tumor-infiltrating MO-MDSCs of CCR5+ Tregs from 7 to 40% (data not shown). Tumor-infiltrating produce high levels of the CCR5 ligands, CCL3, CCL4, and CCL5 MDSC subsets from C57BL/6 mice expressing CD45.2 were sorted by and directly attract Tregs in a CCR5-dependent manner. Accordingly, FACS and placed in 600 ml primary cell medium in the lower wells of an in CCR5-deficient mice, decreased Treg levels were detected in the HTS Transwell-24 (Corning) with a 5-mm pore size. After 18 h, pre- activated Tregs (2 3 105 in 200 ml) were added to the upper chamber and tumor tissue that was associated with delayed tumor growth. Overall, cultured
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