Myeloid-derived suppressor cells (MDSC) display an immature phenotype that may assume a classically activated (M1) or alternatively activated phenotype (M2) in tumors. In this study, we investigated metabolic mechanisms underlying the differentiation of MDSCs into M1 or M2 myeloid lineage and their effect on cancer pathophysiology. We found that SIRT1 deficiency in MDSCs directs a specific switch to M1 lineage when cells enter the periphery from bone marrow, decreasing the suppressive function in favor of a proinflammatory M1 phenotype associated with tumor cell attack. Glycolytic activation through the mTOR-hypoxia-inducible factor1a (HIF-1a) pathway was required for differentiation to the M1 phenotype, which conferred protection against tumors. Our results define the essential nature of a SIRT1-mTOR/HIF-1a glycolytic pathway in determining MDSC differentiation, with implications for metabolic reprogramming as a cancer therapeutic approach. Cancer Res; 74(3); 727-37. Ó2013 AACR.

The differentiation of naive CD4+ T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (TH1) cells and antiinflammatory Foxp3+ regulatory T cells (Treg cells). Genetic deletion of SIRT1 in DCs restrained the generation of Treg cells while driving TH1 development, resulting in an enhanced T-cell–mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGF-β1. Our studies implicates a DC-based SIRT1–HIF1α metabolic checkpoint in controlling T-cell lineage specification.

SummaryThe critical roles of kinase AKT in tumour cell proliferation, apoptosis and protein synthesis have been widely recognized. But AKT also plays an important role in immune modulation. Recent studies have confirmed that kinase AKT can regulate the development and functions of innate immune cells (neutrophil, macrophage and dendritic cell). Studies have shown that different isoforms of kinase AKT have different effects in regulating immunity-related diseases, mainly through the mammalian target of rapamycin-dependent or -independent pathways. The purpose of this review is to illustrate the immune modulating effects of kinase AKT on innate immune cell development, survival and function.

Whereas GCs have been demonstrated to be beneficial for transplantation patients, the pharmacological mechanisms remain unknown. Herein, the role of GR signaling was investigated via a pharmacological approach in a murine allogeneic skin transplantation model. The GC Dex, a representative GC, significantly relieved allograft rejection. In Dex-treated allograft recipient mice, CD11b(+)Gr1(+) MDSCs prolonged graft survival and acted as functional suppressive immune modulators that resulted in fewer IFN-γ-producing Th1 cells and a greater number of IL-4-producing Th2 cells. In agreement, Dex-treated MDSCs promoted reciprocal differentiation between Th1 and Th2 in vivo. Importantly, the GR is required in the Dex-induced MDSC effects. The blocking of GR with RU486 significantly diminished the expression of CXCR2 and the recruitment of CD11b(+)Gr1(+) MDSCs, thereby recovering the increased MDSC-suppressive activity induced by Dex. Mechanistically, Dex treatment induced MDSC iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated the MDSC-suppressive function and the effects on T cell differentiation. This study shows MDSCs to be an essential component in the prolongation of allograft survival following Dex or RU486 treatment, validating the GC-GR-NO signaling axis as a potential therapeutic target in transplantation.