Abstract
Myeloid-derived suppressor cells (MDSC) emerged as major factors driving the tumor progression due to numerous immunosuppressive mechanisms they possess. Prostaglandin (PG)E2 is shown critical for the induction of MDSC and their suppressive functions in vivo, but it is poorly understood how it affects the capacity of MDSC to induce different subsets of regulatory T cells (Treg). By using a novel protocol for the generation of mononuclear (M)-MDSC, we showed that PGE2 potentiates the GM-CSF/IL-6-dependent induction of CD33+CD11b+HLA-DR−CD14+ M-MDSC in vitro. PGE2 diminished the capacity of GM-CSF/IL-6 M-MDSC to produce proinflammatory cytokines upon activation and augmented their capacity to produce IL-27, IL-33, and TGF-β. These results correlated with an increased potential of GM-CSF/IL-6/PGE2 M-MDSC to suppress T cell proliferation, expand alloreactive Th2 cells, and reduce the development of alloreactive Th17 and cytotoxic T cells. Interestingly, GM-CSF/IL-6/PGE2 M-MDSC displayed a lower capacity to induce TGF-β-producing FoxP3+ regulatory Treg compared to GM-CSF/IL-6 M-MDSC, as a consequence of reduced IDO-1 expression. In contrast, GM-CSF/IL-6/PGE2 M-MDSC potentiated IL-10 production by CD8+T, Th2, and particularly CD4+FoxP3− type 1 Treg, the latter of which depended on ILT3 and ILT4 expression. Cumulatively, PGE2 potentiated the suppressive phenotype and functions of GM-CSF/IL-6-induced M-MDSC and changed the mechanisms involved in Treg induction, which could be important for investigating new therapeutic strategies focused on MDSC-related effects in tumors and autoimmune diseases.
Highlights
Cancer immunotherapy has been improved significantly by the discovery of checkpoint inhibitors targeting cytotoxic T leukocyte antigen (CTLA)-4 and programmed death (PD)-1 axis
magnetic-activated cell sorting (MACS)-sorted CD14+ monocytes from healthy donors that were used for differentiation, contained
After their differentiation with GM-CSF and IL-6, up to 34% (23.9 ± 10.2%) of cells showed HLADR−CD14+CD33+CD11b+ M-MDSC phenotype (Figure 1A), and no significant percentage of CD15+ cells was present in the population
Summary
Cancer immunotherapy has been improved significantly by the discovery of checkpoint inhibitors targeting cytotoxic T leukocyte antigen (CTLA)-4 and programmed death (PD)-1 axis. Myeloid-derived suppressor cells (MDSC), which are heterogeneous cell population present in virtually all individuals with a diagnosed tumor [2, 3], have been recognized as major suppressors of the anti-tumor response, and a major limiting factor for the efficacy of checkpoint inhibition therapy [2, 4, 5]. MDSC utilize different suppressive mechanisms to limit the activation of immune cells, of cytotoxic T cells [7], which are the major effector cells in anti-tumor response [8]. The mononuclear subtype (M-MDSC) express a monocytic CD14 marker, whereas polymorphonuclear subtype (PMN-MDSC) express CD15 [9] These subtypes display different suppressive mechanisms, the studies on tumor models in mice suggested that M-MDSC exhibit a stronger immunosuppressive potential compared to PMN-MDSC [10]. It was shown that the induction of tolerance to kidney, skin and cardiac allografts is associated with infiltration of grafts by MDSC [15, 16]
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