title: Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth.
abstract: 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 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 chemokines 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.
authors.affiliation: Innate Immunity, Research Program Tumor Immunology, German Cancer Research Center, Heidelberg D-69120, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Schlecker
authors.forename: Ana
authors.initials: A
authors.lastname: Stojanovic
authors.forename: Christian
authors.initials: C
authors.lastname: Eisen
authors.forename: Christian
authors.initials: C
authors.lastname: Quack
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.forename: Adelheid
authors.initials: A
authors.lastname: Cerwenka
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D054407:Chemokine CCL4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008223:Lymphoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019713:Receptors, CCR5 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D008024:Ligands; D019713:Receptors, CCR5