Mechanism Regulating Reactive Oxygen Species in Tumor-Induced Myeloid-Derived Suppressor Cells

Abstract

Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47phox and gp91phox, compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

“…20 Moreover, Gr-1 1 CD11b 1 myeloid cells directly suppress T-cell immunity by Nox-2-mediated generation of ROS. 21 Carcinoma-associated fibroblasts may also participate in cancer immunology. These cells produce CXCL12 (stromal cell-derived factor-1), VEGF and MMP9.…”

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

“…17,22 In addition, Myd88-dependent NADPH oxidase activation, an important mechanism of MDSC suppressive function, is significantly diminished in TLR4-and Myd88-deficient mice. 41 It is of special interest that, in our experiments, TNF-a secretion in tumor-draining LN CD4 þ T cells was significantly increased in Myd88 À/À mice as compared with WT mice, suggesting that CD4 þ T cells existing in tumor draining LNs of Myd88 À/À mice were responsive to restimulation, but not CD4 þ T cells from WT tumor-bearing mice.…”

“…In addition, TLR2/Myd88-dependent STAT3 activation by Hsp72 on tumor-derived exosomes was reported to be important for the immunosuppressive function of MDSCs. 22 Furthermore, STAT3-dependent expression of NADPH oxidase 41 has been reported; this mediates ROS production in MDSCs. More recently, C/EBPb was proposed as another transcription factor for the activation and functional suppression of MDSCs.…”

“…Many factors have been previously implicated in the suppressive function of MDSCs, including the generation of reactive oxygen species (ROS) and NO by NADPH oxidase 41 and iNOS, 42 the deprivation of extracellular arginine and cysteine by arginase 42 and cysteine transporter X c À , 43 and Fas. 18 The suppressive function of MDSCs seems to be regulated by several transcription factors, including STAT3 and C/EBPb, and several recent studies have shown the STAT3-regulated suppressive functions of MDSCs.…”

“…24 Briefly, the syngeneic splenocytes were divided into equal numbers and either loaded with 1 lg/ml cytotoxic T lymphocyte (CTL) epitope peptide (human Her-2/neu p63 [TYLPTNASL] peptide or a mixture of E6 [41][42][43][44][45][46][47][48][49][50] [EVYD-FAFRDL] and E7 [49][50][51][52][53][54][55][56][57] [RAHYNIVTF] peptides) or left unpulsed. Peptide-pulsed splenocytes were labeled with chloromethylfluorescein diacetate succinimidyl ester (CFSE; Invitrogen, Carlsbad, CA) at 20 lM, and unpulsed splenocytes were labeled with 2 lM CFSE.…”