CD11b+/Gr-1+ Immature Myeloid Cells Mediate Suppression of T Cells in Mice Bearing Tumors of IL-1β-Secreting Cells

Bailey

Psychoneuroendocrinology

et al. 2008

SummaryFrequent or chronic stress as a result of repeated or persistent exposure to social challenges has been shown to affect the glucocorticoid (GC) responsiveness of immune cells in mice. Lipopolysaccharide-stimulated splenocytes of mice that were repeatedly subjected to social disruption were less sensitive to the anti-inflammatory actions of GC as evident from an increased production of pro-inflammatory cytokines and enhanced cell survival. The development of functional GC resistance was accompanied by the accumulation of GC-insensitive CD11b + cells in the spleen. These cells were shown to exhibit impaired nuclear translocation of the GC receptor and lack of GCinduced suppression of NF-κB. Similar impairments in GC receptor function have been reported after in vitro treatment of various cell lines with interleukin (IL)-1. The aim of this study was to elucidate whether IL-1 is a critical factor for the development of GC resistance in socially stressed mice. In the first experiment, we investigated if repeated social stress alters plasma levels and tissue gene expression of IL-1α and IL-1β. It revealed that recurrent stressor exposure significantly increased splenic and hepatic mRNA expression and the plasma protein level of IL-1β, and hepatic mRNA expression of IL-1α. In the second experiment, IL-1 receptor type 1 (IL1R1)-deficient mice were subjected to the stressor and both the tissue distribution of CD11b + cells and the GC sensitivity of the splenocytes were compared to wildtype mice. Mice lacking the IL1R1 exhibited adrenal hypertrophy, thymic involution, and elevated serum corticosterone levels in response to the stressor but did not show splenic accumulation of CD11b + cells and failed to develop GC resistance. These findings suggest that IL-1 plays a critical role in the development of the social stress-associated GC resistance in the murine spleen.

Section: Discussionmentioning

confidence: 96%

Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen

Bailey

Psychoneuroendocrinology

et al. 2008

“…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

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...

The Journal of Immunology

“…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%

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

et al. 2014

150

144

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.