Myeloid-derived suppressor cells: linking inflammation and cancer

Abstract

Many cancer immunotherapies developed in experimental animals have been tested in clinical trials. Although some have shown modest clinical effects, most have not been effective. Recent studies have identified myeloid-origin cells that are potent suppressors of tumor immunity and therefore a significant impediment to cancer immunotherapy. "Myeloid-derived suppressor cells" (MDSC) accumulate in the blood, lymph nodes, and bone marrow and at tumor sites in most patients and experimental animals with cancer and inhibit both adaptive and innate immunity. MDSC are induced by tumor-secreted and host-secreted factors, many of which are proinflammatory molecules. The induction of MDSC by proinflammatory mediators led to the hypothesis that inflammation promotes the accumulation of MDSC that down-regulate immune surveillance and antitumor immunity, thereby facilitating tumor growth. This article reviews the characterization and suppressive mechanisms used by MDSC to block tumor immunity and describes the mechanisms by which inflammation promotes tumor progression through the induction of MDSC.

FIGURE 1

Mouse and human MDSC are heterogeneous populations of immature myeloid cells. Subpopulations of MDSC display different constellations of cell surface and intracellular markers and suppress by different mechanisms. This diversity is likely due to different combinations of factors produced by histologically distinct tumors that cause myeloid cells to arrest at different stages of differentiation.

FIGURE 2

MDSC suppress antitumor immunity through a variety of diverse mechanisms. T cell activation is suppressed by the production of arginase and ROS, the nitration of the TCR, cysteine deprivation, and the induction of Tregs. Innate immunity is impaired by the down-regulation of macrophage-produced IL-12, the increase in MDSC production of IL-10, and the suppression of NK cell cytotoxicity. Ag presentation is limited by the expansion of MDSC at the expense of DC.

FIGURE 3

MDSC are induced and/or activated by multiple proinflammatory mediators. MDSC accumulate in the blood, bone marrow, lymph nodes, and at tumor sites in response to proinflammatory molecules produced by tumor cells or by host cells in the tumor microenvironment. These factors include PGE₂, IL-1β, IL-6, VEGF, S100A8/A9 proteins, and the complement component C5a.