Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression

Bunt, Stephanie K.; Sinha, Pratima; Clements, Virginia K.; Leips, Jeff; Ostrand‐Rosenberg, Suzanne

doi:10.4049/jimmunol.176.1.284

Cited by 498 publications

(479 citation statements)

References 35 publications

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“…The expression of genes encoding inducible NO synthase (iNOS), arginase-1 (Arg-1), vascular endothelial growth factor, matrix metallopeptidase 9 (MMP9), S100A8, and S100A9 were quantitatively measured and compared with the mRNA expression of the housekeeping gene GAPDH. According to previously published data, iNOS and Arg-1 gene expression are elevated in MDSCs arising in several different mouse tumor models including MSC-2-, CT26-, 4T1-, and 3LL-bearing mice (15,16,(30)(31)(32). These transcripts are also reported to be considerably higher in neutrophils relative to other leukocyte populations (6,11,33).…”

Section: Cd11b + Gr-1 + Cells From Malignant Ascites Are Not Mdscsmentioning

confidence: 74%

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Tomihara

Guo

Shin

et al. 2010

The Journal of Immunology

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Both innate and adaptive immune systems are considered important for cancer prevention, immunosurveillance, and control of cancer progression. It is known that, although both systems initially eliminate emerging tumor cells efficiently, tumors eventually escape immune attack by a variety of mechanisms, including differentiation and recruitment of immunosuppressive CD11b+Gr-1+ myeloid suppressor cells into the tumor microenvironment. However, we show that CD11b+Gr-1+ cells found in ascites of epithelial ovarian cancer-bearing mice at advanced stages of disease are immunostimulatory rather than being immunosuppressive. These cells consist of a homogenous population of cells that morphologically resemble neutrophils. Moreover, like dendritic cells, immunostimulatory CD11b+Gr-1+ cells can strongly cross-prime, augmenting the proliferation of functional CTLs via signaling through the expression of costimulatory molecule CD80. Adoptive transfer of these immunostimulatory CD11b+Gr-1+ cells from ascites of ovarian cancer-bearing mice results in the significant regression of s.c. tumors even without being pulsed with exogenous tumor Ag prior to adoptive transfer. We now show for the first time that adaptive immune responses against cancer can be augmented by these cancer-induced granulocyte-like immunostimulatory myeloid (CD11b+Gr-1+) cells, thereby mediating highly effective antitumor immunity in an adoptive transfer model of immunity.

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Section: Cd11b + Gr-1 + Cells From Malignant Ascites Are Not Mdscsmentioning

confidence: 74%

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Tomihara

Guo

Shin

et al. 2010

The Journal of Immunology

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“…Recently, we showed that neutrophils expand in mammary tumorbearing K14-Cre;Cdh1 F/F ;Trp53 F/F mice because of increased macrophage-derived IL-1β stimulation of the IL-17-G-CSF axis 26 . Ectopic overexpression of IL-1β in tumors derived from cancer cell lines or a genetically engineered gastric cancer model also increases the number of circulating neutrophils [60][61][62][63] . As such, aberrant production of cytokines by tumors or stromal cells can offset the balance of neutrophil retention and release from the bone marrow.…”

Section: Neutrophil Retention and Release From Bone Marrowmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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“…Previous studies have demonstrated that various proinflammatory mediators, such as IL-1b (22,40), IL-6 (23), the bioactive lipid PGE 2 (24), S100A8/A9 (25,41), and complement component C5a (42), are involved in the accumulation and activation of MDSCs in tumor-bearing mice and cancer patients. However, whether TNFa, as a prototype and key proinflammatory cytokine, is also in- volved in this pathological process is still obscure.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, the cell surface phenotype of MDSCs is identified as CD11b + and Gr-1 + . The expansion of MDSCs can be induced by the stimulatory factors of myelopoiesis such as GM-CSF, stem cell factor, and vascular endothelial growth factor (19)(20)(21), released primarily by tumor cells, and the activation of MDSCs is associated with proinflammatory mediators, including IL-1b, IL-6, PGE 2 , and S100A8/9 proteins (22)(23)(24)(25), produced by tumor cells, tumor stroma, and tumor-infiltrating immune cells. For example, IL-1b has been reported to promote tumor progression by increasing the accumulation of MDSCs (22), whereas IL-1R-deficient mice have a delayed accumulation of MDSCs and reduced tumor progression.…”

mentioning

confidence: 99%

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

et al. 2014

The Journal of Immunology

153

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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Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression

Cited by 498 publications

References 35 publications

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Neutrophils in cancer: neutral no more

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

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