Enhanced suppressive capacity of tumor-infiltrating myeloid-derived suppressor cells compared with their peripheral...

Although the main site of action for myeloid-derived suppressor cells (MDSCs) is most likely the tumor microenvironment, so far the study of these cells has been largely restricted to spleen-derived MDSCs. In this study, we compared the suppressive capacity of splenic and tumor-derived MDSCs in different subcutaneous mouse tumor models. We investigated which suppressive mechanisms were involved. Finally, we investigated whether MDSCs and regulatory T cells (Treg ) cooperate in the suppression of T-cell responses. In all models, splenic granulocytic MDSCs (grMDSC) strongly suppress CD4(+) T-cell proliferation while the suppressive effect on CD8(+) T cells is less pronounced. Splenic monocytic MDSCs (moMDSC) have a lower suppressive capacity, compared to grMDSC, on both CD4(+) and CD8(+) T-cell proliferation. Both grMDSC and moMDSC isolated from the tumor have a much stronger suppressive activity compared to MDSCs isolated from the spleen of tumor-bearing mice, associated with a higher NO2 (-) production by the tumor-derived moMDSC and arginase activity for both subsets. The expression of CD80 is also elevated on tumor-derived grMDSC compared with their peripheral counterparts. Direct contact with tumor cells is required for the upregulation of CD80 and CD80(+) MDSCs are more suppressive than CD80(-) MDSCs. Coculture of Treg and MDSCs leads to a stronger suppression of CD8(+) T-cell proliferation compared to the suppression observed by Treg or MDSCs alone. Thus, we showed that tumor-infiltrating MDSCs possess a stronger suppressive capacity than their peripheral counterparts and that various suppressive mechanisms account for this difference.