Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF

Luigi Dolcetti, Elisa Peranzoni, Stefano Ugel, Ilaria Marigo, Audry Fernandez Gomez, Circe Mesa, Markus Geilich, Gregor Winkels, Elisabetta Traggiai, Anna Casati, Fabio Grassi, Vincenzo Bronte

Research output: Contribution to journalArticlepeer-review

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-1 high 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.

Original languageEnglish
Pages (from-to)22-35
Number of pages14
JournalEuropean Journal of Immunology
Volume40
Issue number1
DOIs
Publication statusPublished - Jan 2010

Keywords

  • GM-CSF
  • Immunosuppression
  • Myeloid-derived suppressor cells subsets
  • Tolerance

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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