title: Regulatory T cells stimulate B7-H1 expression in myeloid-derived suppressor cells in ret melanomas.
abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells, and they promote an immunosuppressive environment in tumor-bearing hosts. To characterize MDSCs in melanoma, we examined the expression of inhibitory B7 molecules by CD11b(+)Gr1(+) cells isolated from mice with transplantable ret tumors. B7 molecules were expressed on CD11b(+)Gr1(+) cells, which also expressed CD124 and inducible nitric oxide synthase, thus verifying their relation to MDSCs. In developing melanomas, CD11b(+)Gr1(+) cells express only low levels of B7-H1. In contrast, B7-H1 is upregulated in large tumors, and functional analysis demonstrates that CD11b(+)Gr-1(+) cells suppress the proliferation of CD4(+) T cells through B7-H1. Depletion of regulatory T cells (Tregs) significantly downregulated the expression of B7-H1, B7-H3, and B7-H4 on MDSCs and reduced tumor growth, indicating a concerted immunosuppressive activity of Tregs and MDSCs. No differences in the suppressive function of MDSCs between CD25-depleted and non-depleted mice were recorded. Instead, tumor-derived MDSCs from Treg-depleted hosts produced less IL-10 and more IFN-γ as compared with Treg-harboring mice. These studies indicate that Tregs in tumors not only suppress effector T cells directly, but also modify the phenotype of tumor-infiltrating CD11b(+) cells to express inhibitory B7-H molecules and to produce IL-10.
authors.affiliation: Department of Dermatology, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany. tfujimura1@mac.com
authors.forename: Taku
authors.initials: T
authors.lastname: Fujimura
authors.forename: Sabine
authors.initials: S
authors.lastname: Ring
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.forename: Karsten
authors.initials: K
authors.lastname: Mahnke
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Enk
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*
chemical_list: D060890:B7-H1 Antigen; D039481:CD11b Antigen; D053662:Interleukin-4 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse