CXCR2-Expressing Myeloid-Derived Suppressor Cells Are Essential to Promote Colitis-Associated Tumorigenesis

Katoh, Hiroshi; Wang, Dingzhi; Daikoku, Takiko; Sun, Haiyan; Dey, Sudhansu K.; DuBois, Raymond N.

doi:10.1016/j.ccr.2013.10.009

Cited by 393 publications

(389 citation statements)

References 60 publications

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“…20-22 It has been well recognized, in studies of both pre-clinical and clinical samples, that MDSCs are enriched in the tumor infiltrated tissue in solid tumors. 23,24 In addition, significant expansion of MDSCs in peripheral blood has been reported in patients with multiple myeloma, non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. 25-27 However studies on the contributions of MDSCs to the pathogenesis of AML are scarce.…”

Section: Discussionmentioning

confidence: 99%

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

et al. 2018

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Treatment of acute myeloid leukemia (AML) remains challenging. Enhancement of anti-tumor responses by blocking negative immune regulators is a promising strategy for novel effective leukemia therapeutics. V-domain Ig suppressor of T-cell activation (VISTA) is a recently defined negative regulator mediating immune evasion in cancer. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients. Here we report that VISTA is highly expressed on myeloid-derived suppressor cells (MDSCs) in the peripheral blood of AML patients. Both the frequency and intensity of VISTA expression on MDSCs are significantly higher in newly diagnosed AML than in healthy controls. Importantly knockdown of VISTA by specific siRNA potently reduced the MDSCs-mediated inhibition of CD8 T cell activity in AML, suggesting a suppressive effect of VISTA on anti-leukemia T cell response. Furthermore, we observed a strong positive association between MDSC expression of VISTA and T cell expression of PD-1 in AML. These results support the strategy of VISTA-targeted treatment for AML and underscore the strong potential for combined blockade of VISTA and PD-1 pathways in effective leukemia control.

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Section: Discussionmentioning

confidence: 99%

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

et al. 2018

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“…In addition to IL‐6, IL‐8, and IL‐1β, another ZEB1‐regulated cytokine, G‐CSF/CSF3, also enhances the accumulation of MDSCs (Talmadge and Gabrilovich, 2013). ZEB1 also regulates the expression of the chemokines CXCL1 and CXCL5, which are the ligands for the CXCR2 receptor, and increases the infiltration of PMN‐MDSCs (Acharyya et al ., 2012; Katoh et al ., 2013; Toh et al ., 2011). Although the present study showed no additional effect of ZEB1 on tumor progression or on the metastasis of 4T1 cells, which may be due to the aggressive nature of the parental 4T1 cells, these observations suggest that inflammatory cytokines induced by ZEB1 play critical roles in the progression of cancer in a context‐dependent manner.…”

Section: Discussionmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

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“…Inflammation plays an essential role in initiating tumorigenesis by damaging specific tissues 100 (Figure 3). In these models, neutrophils are attracted to tumor-prone tissues via the CXCR2 ligands, CXCL1, CXCL2 and CXCL5 [101][102][103][104] . Application of these carcinogens to CXCR2-deficient mice, which show impaired neutrophil trafficking, prevents papilloma or adenoma formation 102,104 .…”

Section: Neutrophils and Tumor Initiationmentioning

confidence: 99%

“…In these models, neutrophils are attracted to tumor-prone tissues via the CXCR2 ligands, CXCL1, CXCL2 and CXCL5 [101][102][103][104] . Application of these carcinogens to CXCR2-deficient mice, which show impaired neutrophil trafficking, prevents papilloma or adenoma formation 102,104 . Similarly, CXCR2 ligands are increased in several genetically engineered mouse models, including the intestinal adenoma Apc Min/+ model, the invasive intestinal adenocarcinoma Ah-CreER;Apc F/+ ;Pten F/F model and the spontaneous oral papilloma K14-CreER;Kras G12D/+ model.…”

Section: Neutrophils and Tumor Initiationmentioning

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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CXCR2-Expressing Myeloid-Derived Suppressor Cells Are Essential to Promote Colitis-Associated Tumorigenesis

Cited by 393 publications

References 60 publications

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

ZEB1‐regulated inflammatory phenotype in breast cancer cells

Neutrophils in cancer: neutral no more

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