Figure 9

Schematic for the induction of human CD33⁺ and CD11b⁺ MDSC in cancer. A, Hypoxia and tumor-derived cytokines IL-1β, IL-6, TNFα, VEGF, FLT3L, and TGFβ in the tumor microenvironment promote signaling through STAT3, NFκB/C/EBPβ, SMAD2/4, and HIF1α pathways in myeloid cells. In addition to oxygen-dependent HIF1α regulation, inflammatory cytokines up-regulate HIF1α transcription (via PI3K or MAPK) and NO stabilizes HIF1α protein (via S-nitrosylation). Other factors influencing MDSC function include PBMC and tumor-derived GM-CSF, which supports expansion of myeloid progenitors and survival of MDSC, and IFNγ, which contributes to MDSC activation. Transactivation (*) between JAK/STAT, HIF1α, and NFκB signaling pathways amplifies the induction effects of tumor-derived cytokines and hypoxia in MDSC. B, Activated transcription factors translocate to the nucleus where they up-regulate expression of suppressive genes (iNOS, NOX2, ARG-1, VEGF) and autocrine production of putative MDSC inducers (e.g. IL-6, IL-1β, TNFα, and VEGF). The transcription factors driving suppressive function (and by extension potential therapeutic targets) in human MDSC appear to vary by subset, with a dominant role for STAT3 and HIF1α in CD33⁺ MDSC (purple) and a dominant role for NFκB-C/EBPβ in CD11b⁺ MDSC (pink).