Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis

Ibrahim, Mohammed L.; Klement, John D.; Lu, Chunwan; Redd, Priscilla S.; Xiao, Wei; Yang, Dafeng; Browning, Darren D.; Savage, Natasha M.; Buckhaults, Phillip; Morse, Herbert C.; Liu, Kebin

doi:10.1016/j.celrep.2018.11.050

Cited by 67 publications

(54 citation statements)

References 41 publications

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“…Previous work in our laboratory has demonstrated that IRF8 expression is reduced in both MDSC subsets and their progenitors in mouse models of mammary carcinoma (39,40). These findings have been recapitulated by other investigators examining a number of solid tumors and hematologic malignancies (41)(42)(43). Tumor-driven downregulation of IRF8 was found to dysregulate myelopoiesis at least in part by promoting the expansion of tumor-derived GPs, which selectively led to PMN-MDSCs.…”

Section: Transcriptional Regulators Of Pmn-mdscssupporting

confidence: 73%

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Kramer

Abrams

2020

Front. Immunol.

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The immune system plays a critical role in cancer progression and response to therapy. However, the immune system can be compromised during the neoplastic process. Notably, the myeloid lineage, which gives rise to granulocytic cells, including neutrophils, is a well-recognized target of tumor-mediated immune suppression. Ordinarily, granulocytic cells are integral for host defense, but in neoplasia the normal process of granulocyte differentiation (i.e., granulopoiesis) can be impaired leading instead to the formation of granulocytic (or PMN)-myeloid-derived suppressor cells (MDSCs). Such cells comprise various stages of myeloid differentiation and are defined functionally by their highly pro-tumorigenic and immune suppressive activities. Thus, considerable interest has been devoted to impeding the negative contributions of PMN-MDSCs to the antitumor response. Understanding their biology has the potential to unveil novel therapeutic opportunities to hamper PMN-MDSC production in the bone marrow, their mobilization, or their effector functions within the tumor microenvironment and, therefore, bolster anticancer therapies that require a competent myeloid compartment. In this review, we will highlight mechanisms by which the neoplastic process skews granulopoiesis to produce PMN-MDSCs, summarize mechanisms by which they execute their pro-tumorigenic activities and, lastly, underscore strategies to obstruct their role as negative regulators of antitumor immunity.

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Section: Transcriptional Regulators Of Pmn-mdscssupporting

confidence: 73%

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Kramer

Abrams

2020

Front. Immunol.

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“…Journal of Immunology Research to silencing of tumor suppressor IRF8 in colonic epithelial cells, to promote colitis-associated colon tumorigenesis [41], while Lin et al showed that liver metastasis in CRC patients could be initiated by MDSCs [42]. Our results indicate that the different myeloid cell subsets contribute to tumor progression in unique pathways since not all potential MDSC subpopulations were elevated in circulation or TME or associated with disease staging, tumor budding, or LVI in CRC patients.…”

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confidence: 63%

Myeloid Cells in Circulation and Tumor Microenvironment of Colorectal Cancer Patients with Early and Advanced Disease Stages

Toor

Khalaf

Murshed

et al. 2020

Journal of Immunology Research

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Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells that have been implicated in the development of an immunosuppressive environment, which promotes tumorigenesis and tumor progression. Numerous studies have reported expansion of MDSCs in circulation and the tumor microenvironment (TME) of cancer patients. However, due to the heterogenic nature of MDSCs and the different approaches for their identification, their detailed characterization and impact on disease progression in cancer patients are warranted. In this study, we investigated the levels of different myeloid cell subsets and antigen-presenting cells (APCs) using flow cytometry in unfractionated whole blood (WB), peripheral blood mononuclear cells (PBMCs), tumor tissue (TT), and adjacent normal tissue (NT) of colorectal cancer (CRC) patients. We found high levels of granulocytic myeloid cells (GMCs) in whole blood, but their levels were significantly lower in PBMCs. Importantly, we found significantly higher levels of GMCs in the TME compared to NT. In addition, monocytic myeloid cells (MMCs) showed significantly higher levels in PBMCs of CRC patients, compared to healthy donors (HDs). Notably, patients with advanced disease stages showed significantly higher levels of GMCs compared to early stages in whole blood, but PBMCs and tumor-infiltrating myeloid cells did not show any significant differences. Lastly, we found that levels of GMCs decreased, while IMCs increased in the TME with tumor budding. Our results highlight the importance of investigating the levels of different myeloid cell subsets in PBMCs versus whole blood of cancer patients and improve current knowledge on the potential prognostic significance of myeloid cells in CRC patients.

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“…A previous study indicated that USF2 is associated with tumor grade and inversely with survival in Stage II colon cancers [54]. IRF1 and IRF8 are member of the IFN regulatory factor family; both of them were proven to be suppressor of colon cancer [55,56]. Fijneman and colleagues found a set of RUNX1 target genes in mouse colon indicative of changes in gut homeostasis, that is, genes involved in inflammation and intestinal metabolism, which are known to increase the risk of tumor development [57].…”

Section: Discussionmentioning

confidence: 99%

WGCNA reveals key gene modules regulated by the combined treatment of colon cancer with PHY906 and CPT11

Xing

Wang

et al. 2020

Bioscience Reports

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Irinotecan (CPT11) is one of the most effective drugs for treating colon cancer, but its severe side effects limit its application. Recently, a traditional Chinese herbal preparation, named PHY906, has been proved to be effective for improving therapeutic effect and reducing side effects of CPT11. The aim of this study was to provide novel insight to understand the molecular mechanism underlying PHY906-CPT11 intervention of colon cancer. Based on the GSE25192 dataset, for different three treatments (PHY906, CPT11, and PHY906-CPT11), we screened out differentially expressed genes (DEGs) and constructed a co-expression network by weighted gene co-expression network analysis (WGCNA) to identify hub genes. The key genes of the three treatments were obtained by merging the DEGs and hub genes. For the PHY906-CPT11 treatment, a total of 18 key genes including Eif4e, Prr15, Anxa2, Ddx5, Tardbp, Skint5, Prss12 and Hnrnpa3, were identified. The results of functional enrichment analysis indicated that the key genes associated with PHY906-CPT11 treatment were mainly enriched in “superoxide anion generation” and “complement and coagulation cascades”. Finally, we validated the key genes by GEPIA and RT-PCR analysis, the results indicated that EIF4E, PRR15, ANXA2, HNRNPA3, NCF1, C3AR1, PFDN2, RGS10, GNG11, and TMSB4X might play an important role in the treatment of colon cancer with PHY906-CPT11. In conclusion, a total of 18 key genes were identified in this study. These genes showed strong correlation with PHY906-CPT11 treatment in colon cancer, which may help elucidate the underlying molecular mechanism of PHY906-CPT11 treatment in colon cancer.

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Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis

Cited by 67 publications

References 41 publications

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Myeloid Cells in Circulation and Tumor Microenvironment of Colorectal Cancer Patients with Early and Advanced Disease Stages

WGCNA reveals key gene modules regulated by the combined treatment of colon cancer with PHY906 and CPT11

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