Tumor Necrosis Factor-α Blocks Differentiation and Enhances Suppressive Activity of Immature Myeloid Cells during Chronic Inflammation

Abstract

Elevated concentrations of tumor necrosis factor-α (TNF-α) are detected in pathologies characterized by chronic inflammation. Whether TNF-α plays a role in manipulating the host's immune system toward generating an immunosuppressive milieu, typical of ongoing chronic inflammation, is unclear. Here we showed that TNF-α exhibited a dual function during chronic inflammation: arresting differentiation of immature myeloid-derived suppressor cells (MDSCs) primarily via the S100A8 and S100A9 inflammatory proteins and their corresponding receptor (RAGE) and augmenting MDSC suppressive activity. These functions led to in vivo T and NK cell dysfunction accompanied by T cell antigen receptor ζ chain downregulation. Furthermore, administration of etanercept (TNF-α antagonist) during early chronic inflammatory stages reduced MDSCs' suppressive activity and enhanced their maturation into dendritic cells and macrophages, resulting in the restoration of in vivo immune functions and recovery of ζ chain expression. Thus, TNF has a fundamental role in promoting an immunosuppressive environment generated during chronic inflammation.

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

“…The tumorigenic TNF-R1-dependent TNF signaling may not be restricted to a direct effect on CD8 þ T cells; it could also involve additional cell types of the tumor microenvironment. TNF has been recently shown to facilitate the accumulation of Treg (41) and MDSC (30,31), the latter exhibiting granulocytic phenotype in cancer (42). Upon B16K1 cell injection, the tumor content of Treg and MDSC did not decrease in TNF-deficient mice, indicating that under our experimental conditions, TNF is unlikely a critical cytokine for accumulating those immunosuppressor cells into the tumors.…”

Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab

“…In mice, depletion of MDSCs by anti-Gr1 antibodies leads to immune system recuperation that increases efficacy of immune-based therapies (13) as well as to tumor regression (Sade-Feldman and colleagues; unpublished data). Along this strategy, anti-CD33 antibodies currently used for therapy of patients with myeloid leukemia (43) could be used to deplete human CD33 positive MDSCs to increase immune system efficacy.…”

“…In both mice and humans, the expansion and activation of MDSCs is mediated by a complex network of proinflammatory cytokines, chemokines, and growth factors, persistently secreted by normal or modified cells, including tumor cells (12)(13)(14). In mice, these cells are identified as GR1 þ CD11b þ cells and can been further subdivided into two main subsets with different phenotypic and biologic properties, the monocytic MDSCs (Mo-MDSC) characterized by CD11b þ Ly6G À Ly6C high and granulocytic like MDSCs (G-MDSC) expressing CD11b þ Ly6G þ Ly6C low (10,12).…”

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

“…5D). MDSCs could be induced to differentiating into mature myeloid cells under proper conditions (20). Splenic CD11b ϩ Gr1 ϩ cells with ATF3 deletion clearly had a lower ability to differentiate into mature myeloid cells when cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 (Fig.…”