Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis

Abstract

Myeloid-derived suppressor cells (MDSCs IntroductionA major barrier to effective cancer immunotherapy is immune suppression, and the accumulation of myeloid-derived suppressor cells (MDSCs) has recently been recognized as a major mechanism to promote immune suppression (1, 2). MDSCs comprise a mixture of myeloid cells reflecting various stages of differentiation, and in mouse models, these cells are typically distinguished from other inhibitory myeloid populations based on their unique coexpression of macrophage (CD11b) and granulocyte (Gr-1) markers (1).Tumor-induced MDSCs are further dichotomized into monocytic and granulocytic subsets based on the differential expression of the Ly6G and Ly6C epitopes (3, 4). Intriguingly, granulocytic MDSCs outnumber monocytic MDSCs in numerous mouse tumor models (3, 5), although the basis for this subset dichotomy remains unclear. The phenotypes in humans are more complex and vary with tumor type. However, there is general agreement that a common lineage-negative MDSC subset observed among a range of human cancers bears the core phenotype CD33 + HLA-DR -(6-11). Interestingly, this subset resembles promyelocytes, a granulocytic population reflecting an early stage of differentiation (6, 7).Although many studies have been dedicated to the phenotypic characterization of MDSCs and unraveling mechanisms by which these cells mediate tumor progression, a large gap remains in our understanding of the mechanisms that initiate their development. It is known, however, that MDSC subsets emerge in response to tumor-derived factors (TDFs) and the signaling pathways these molecules engage. As a number of TDFs engage the STAT3 or STAT5 signaling pathway, STAT3 or STAT5 activation has been associated with various stages in MDSC biology (1,(12)(13)(14)(15)(16)(17)(18)(19).

Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells

“…Interestingly, there appears to be a consensus regarding activation of Janus kinase protein and STAT 3 and 5 (47). Indeed, some reports argue that STAT 3 and 5 regulate MDSC function in both mice and humans (9,10,48 (20). Thus, these findings appear to be important in terms of MDSC induction by mTOR inhibitors or other immunosuppressive drugs in the context of clinical organ transplantation.…”

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

“…The levels of CD45.2 ϩ cell, CD11b ϩ Gr1 ϩ cell, and BrdU ϩ cell were evaluated by flow cytometry. MDSC Depletion-G-MDSC depletion was performed as described previously (44). Briefly, anti-Ly6G antibody (1A8) or anti-IgG antibody (rat IgG2b) was injected (120 g per injection) through the tail vein on days 0 and 3 at post-Dex injection.…”

Neutrophils in cancer: neutral no more

“…Transforming growth factor β (TGFβ), G-CSF and interferon β (IFNβ) are the most well-studied molecules in this process. TGFβ and G-CSF activate a tumor-and metastasispromoting program 25,27,65,[85][86][87][88] , by regulating the transcription factors inhibitor of DNA 1 (ID1), retinoblastoma 1 (RB1) and interferon regulatory factor 8 (IRF8) that control the immunosuppressive functions of neutrophils 25,87,89,90 . IFNβ acts as a negative regulator of the pro-tumorigenic phenotype of neutrophils 91,92 .…”

“…Neutropenia predisposes patients to life-threatening infections, therefore recombinant G-CSF or GM-CSF is commonly prescribed to counteract reduced neutrophil numbers brought on by chemotherapy and to lessen therapy-induced mortality 190,191 . However, experimental studies indicate that G-CSF polarizes neutrophils towards a pro-tumorigenic phenotype and promotes metastasis formation [25][26][27][28]87 . Two experimental studies examining tumor growth after combining chemotherapy with G-CSF neutralization reported contradictory results 28,192 , leaving the debate open.…”