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

Top Cited Papers
Open Access
Publisher Website
Google Scholar
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.