title: Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF.
abstract: CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) contribute to tumor immune evasion by restraining the activity of CD8+ T-cells. Two major MDSC subsets were recently shown to play an equal role in MDSC-induced immune dysfunctions: monocytic- and granulocytic-like. We isolated three fractions of MDSC, i.e. CD11b+/Gr-1high, CD11b+/Gr-1int, and CD11b+/Gr-1low populations that were characterized morphologically, phenotypically and functionally in different tumor models. In vitro assays showed that CD11b+/Gr-1int cell subset, mainly comprising monocytes and myeloid precursors, was always capable to suppress CD8+ T-cell activation, while CD11b+/Gr-1high cells, mostly granulocytes, exerted appreciable suppression only in some tumor models and when present in high numbers. The CD11b+/Gr-1int but not CD11b+/Gr-1high cells were also immunosuppressive in vivo following adoptive transfer. CD11b+/Gr-1low cells retained the immunosuppressive potential in most tumor models. Gene silencing experiments indicated that GM-CSF was necessary to induce preferential expansion of both CD11b+/Gr-1int and CD11b+/Gr-1low subsets in the spleen of tumor-bearing mice and mediate tumor-induced tolerance whereas G-CSF, which preferentially expanded CD11b+/Gr-1high cells, did not create such immunosuppressive environment. GM-CSF also acted on granulocyte-macrophage progenitors in the bone marrow inducing local expansion of CD11b+/Gr-1low cells. These data unveil a hierarchy of immunoregulatory activity among MDSC subsets that is controlled by tumor-released GM-CSF.
authors: Istituto Oncologico Veneto, Padova, Italy.
authors: Luigi
authors: L
authors: Dolcetti
authors: Elisa
authors: E
authors: Peranzoni
authors: Stefano
authors: S
authors: Ugel
authors: Ilaria
authors: I
authors: Marigo
authors: Audry
authors: A
authors: Fernandez Gomez
authors: Circe
authors: C
authors: Mesa
authors: Markus
authors: M
authors: Geilich
authors: Gregor
authors: G
authors: Winkels
authors: Elisabetta
authors: E
authors: Traggiai
authors: Anna
authors: A
authors: Casati
authors: Fabio
authors: F
authors: Grassi
authors: Vincenzo
authors: V
authors: Bronte
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000276:immunology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology; D034622:RNA Interference; D019707:Receptors, Chemokine / Q000276:immunology*
chemical_list: D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor