Transcription factors in myeloid-derived suppressor cell recruitment and function

Sonda, Nada; Chioda, Mariacristina; Zilio, Serena; Simonato, Francesca; Bronte, Vincenzo

doi:10.1016/j.coi.2010.12.006

Cited by 55 publications

(46 citation statements)

References 46 publications

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“…The second step triggered by molecules such as IFN-g, IL-1b, and TLR ligands uses STAT1 and NF-kB transcription factors and upregulates arginase and NO. Separately, Bronte and colleagues (35) have suggested that the family of C/EBPb transcription factors along with STAT proteins regulate shift from normal to aberrant hematopoiesis, allowing differentiation into MDSCs, as well as their recruitment and activation. In proposing a novel mechanism of increased MDSC numbers, Ostrand-Rosenberg et al (36) suggested that MDSC levels in developing tumors is maintained by resistance to apoptosis by FasL + expressing activated T cells.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells

Husain

Huang

Seth

et al. 2013

The Journal of Immunology

607

473

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In this study, we explore the hypothesis that enhanced production of lactate by tumor cells, because of high glycolytic activity, results in inhibition of host immune response to tumor cells. Lactate dehydrogenase-A (LDH-A), responsible for conversion of pyruvate to lactate, is highly expressed in tumor cells. Lentiviral vector–mediated LDH-A short hairpin RNA knockdown Pan02 pancreatic cancer cells injected in C57BL/6 mice developed smaller tumors than mice injected with Pan02 cells. A decrease occurred in the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying LDH-A–depleted tumors. NK cells from LDH-A–depleted tumors had improved cytolytic function. Exogenous lactate increased the frequency of MDSCs generated from mouse bone marrow cells with GM-CSF and IL-6 in vitro. Lactate pretreatment of NK cells in vitro inhibited cytolytic function of both human and mouse NK cells. This reduction of NK cytotoxic activity was accompanied by lower expression of perforin and granzyme in NK cells. The expression of NKp46 was decreased in lactate-treated NK cells. These studies strongly suggest that tumor-derived lactate inhibits NK cell function via direct inhibition of cytolytic function as well as indirectly by increasing the numbers of MDSCs that inhibit NK cytotoxicity. Depletion of glucose levels using a ketogenic diet to lower lactate production by glycolytic tumors resulted in smaller tumors, decreased MDSC frequency, and improved antitumor immune response. These studies provide evidence for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity.

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Section: Discussionmentioning

confidence: 99%

Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells

Husain

Huang

Seth

et al. 2013

The Journal of Immunology

607

473

View full text Add to dashboard Cite

show abstract

“…These factors are critical not only in the expansion of MDSCs, but also, more importantly, in their functional activation. Both processes are mainly regulated by the same set of transcription factors, i.e., STAT3, STAT1, STAT6, and NF-κB (36,37). Blockade of factors such as S100A8/9 impairs MDSC accumulation (34).…”

Section: Discussionmentioning

confidence: 99%

TNF signaling drives myeloid-derived suppressor cell accumulation

Zhao¹,

Rong²,

Zhao³

et al. 2012

J. Clin. Invest.

314

275

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“…This population of cells is markedly increased in tumor-bearing hosts and suppresses antitumor immune response through multiple mechanisms (16)(17)(18), including high activity of arginase-1 (ARG1) and/or inducible NO synthase (iNOS), production of NO and reactive oxygen species (ROS), as well as release of IL-10 and TGF-b. In mice, the cell surface phenotype of MDSCs is identified as CD11b + and Gr-1 + .…”

mentioning

confidence: 99%

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

et al. 2014

The Journal of Immunology

150

144

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It has been reported that TNFR2 is involved in regulatory T cell induction and myeloid-derived suppressor cell (MDSC) accumulation, two kinds of immunosuppressive cells contributing to tumor immune evasion. Because transmembrane TNF-α (tmTNF-α) is the primary ligand for TNFR2, we hypothesized that tmTNF-α is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF-α, rather than secretory TNF-α (sTNF-α), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-β, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF-α was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-α–induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF-α caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-α–mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF-α mutant by 4T1 cells significantly promoted tumor progression and angiogenesis, accompanied with more accumulation of MDSCs and regulatory T cells in the tumor site, increased production of NO, IL-10, and TGF-β, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF-α mutant by 4T1 cells that only released sTNF-α without expression of surface tmTNF-α markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF-α acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.

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Transcription factors in myeloid-derived suppressor cell recruitment and function

Cited by 55 publications

References 46 publications

Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells

Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells

TNF signaling drives myeloid-derived suppressor cell accumulation

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

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