Dual Negative Roles of C/EBPα in the Expansion and Pro-angiogenic Function of Myeloid-Derived Suppressor Cells

Abstract

Myeloid-derived suppressor cells (MDSCs) play an important role in cancer progression. Elucidating the mechanisms involved in the expansion and function of these cells is important in the fight against cancer. A microarray comparing splenic Gr-1+CD11b+ cells from tumor-bearing mice and tumor-free mice revealed C/EBPα expression was reduced more than 4-fold in the tumor-derived cells. Based on this finding and published reports, we hypothesized that tumors induce MDSC production through down-regulation of C/EBPα in myeloid cells. In Chapter II, the role of C/EBPα as a negative regulator of MDSC expansion was investigated. Deletion of myeloid C/EBPα in mice yielded an increase in myeloid progenitors and a reduction in mature myeloid cells. Upon inoculation with tumor cells, MDSC production was enhanced nearly two-fold in mice lacking myeloid C/EBPα, while myeloid progenitors were reduced, perhaps because more progenitors became MDSCs in the absence of C/EBPα. In Chapter III, we sought to determine whether C/EBPα is a negative regulator of the immune suppressive and pro-angiogenic properties of MDSCs. When inoculated with tumor cells, MDSC infiltration and tumor vascularization was significantly greater in C/EBPα conditional null mice, resulting in markedly accelerated tumor growth. When MDSCs were injected with tumor cells into mice, C/EBPα ablation resulted in an enhancement in the pro-tumor MDSC phenotype: tumor growth and tumor angiogenesis was significantly greater. We then measured the expression of genes involved in MDSC-mediated immune suppression and angiogenesis and found that C/EBPα deletion resulted in MMP-9, VEGF and iNOS upregulation. Additionally, we observed increased NO production but no difference in arginase expression or immune suppression. Since NO also regulates angiogenesis, we concluded that C/EBPα inhibits the pro-angiogenic but not the immune-suppressive properties of MDSCs. Our findings reveal dual negative roles for C/EBPα in the expansion and pro-angiogenic gene expression in MDSCs, suggesting that overcoming these functions through C/EBPα inhibition may be a critical step in MDSC maturation. Our work indicates that therapy aimed at restoring C/EBP expression in MDSCs may be a viable weapon in the fight against cancer.