Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells

Donkor, Moses; Lahue, E E; Hoke, Traci; Shafer, Laura; Coşkun, Uğur; Solheim, Joyce C.; Gülen, Dumrul; Bishay, John; Talmadge, James E.

doi:10.1016/j.intimp.2009.03.021

Cited by 94 publications

(87 citation statements)

References 40 publications

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“…7). In contrast to the majority of reports, which used xenograft and allograft models (19,39,40), our endogenous model indicates that MDSC expansion occurs solely in the prostate during disease initiation and progression. There is no significant expansion of Gr-1 ϩ CD11b ϩ cells in the lymph nodes, spleen, liver, or bone marrow of these same tumorbearing mice.…”

Section: Discussioncontrasting

confidence: 76%

Pten Null Prostate Epithelium Promotes Localized Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Tumor Initiation and Progression

Garcia

Ruscetti

Arenzana

et al. 2014

Molecular and Cellular Biology

122

124

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f Chronic inflammation is known to be associated with prostate cancer development, but how epithelium-associated cancer-initiating events cross talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1 ؉ CD11b ؉ myeloid-derived suppressor cells (MDSCs) occurring intraprostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1 ؉ CD11b ؉ cells, but not those isolated from the spleen of the same tumor-bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, the loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf1 and Il1b, two genes known to induce MDSC expansion and immunosuppressive activities. Treatment of Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epitheliumassociated tumor-initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression.

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Section: Discussioncontrasting

confidence: 76%

Pten Null Prostate Epithelium Promotes Localized Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Tumor Initiation and Progression

Garcia

Ruscetti

Arenzana

et al. 2014

Molecular and Cellular Biology

122

124

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“…MDSC can inhibit T cells and dendritic cells, contributing to tumor immune escape. The MDSC in the peripheral blood, spleen and tumors are directly associated with mammary tumor sizes and inversely correlated with the T cell number (Abe et al 2010;Donkor et al 2009). TGF-β binds to MDSC, leading to MDSCmediated suppression of natural killer (NK) cells.…”

Section: Immune Cellsmentioning

confidence: 99%

Transforming growth factor-β signaling in tumor initiation, progression and therapy in breast cancer: an update

Zhang

Cao

et al. 2011

Cell Tissue Res

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Transforming growth factor-β (TGF-β) is a ubiquitous cytokine playing an essential role in cell proliferation, differentiation, apoptosis, adhesion and invasion, as well as in cellular microenvironment. In malignant diseases, TGF-β signaling features a growth inhibitory effect at an early stage but aggressive oncogenic activity at the advanced malignant state. Here, we update the current understanding of TGF-β signaling in cancer development and progression with a focus on breast cancer. We also review the current approaches of TGF-β signaling-targeted therapeutics for human malignancies.

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“…An important mechanism through which cancers escape immune destruction is via recruitment or induction of suppressor immune cells, including regulatory T cells (Treg) and myeloidderived suppressor cells (MDSC) (20)(21)(22). Human MDSC are a heterogeneous population of immature myeloid cells that inhibit T cell effector function through a range of mechanisms, such as arginase-1 and inducible nitric oxide synthase (23)(24)(25). While rare in healthy individuals, MDSC may accumulate in the settings of severe trauma, sepsis, or cancer (26).…”

Section: Introductionmentioning

confidence: 99%

Circulating Myeloid-Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent

Angell

Lechner

Smith

et al. 2016

Thyroid

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Background: Establishing the preoperative diagnosis and long-term prognosis of differentiated thyroid cancer (DTC) remain challenging in some patients. Myeloid-derived suppressor cells (MDSC) are tumor-induced cells mediating immune tolerance that are detectable in the peripheral blood of cancer patients. The authors previously developed a novel clinical assay to detect the phenotypes of two human MDSC subsets in peripheral blood, and hypothesize that higher MDSC levels measured by this assay correlate positively with both ma-lignancy and worse patient outcomes. Methods: A prospective observational pilot study was performed of patients undergoing thyroidectomy for a solitary thyroid nodule. The presence of a thyroid nodule >1 cm was confirmed sonographically, and fine-needle aspiration biopsy performed prior to surgery in all cases. Peripheral blood collected preoperatively was analyzed using a novel flow cytometry-based immunoassay to detect and quantify two subsets of human MDSC. Circulating MDSC levels were compared by histopathologic diagnosis, stage, and presence of persistent disease after treatment. Results: Of 50 patients included in this study, MDSC measurement was successful in 47 (94%). One patient was found to have a concurrent cancer, leaving 46 patients for primary analysis. The cytologic diagnoses were benign in five (10.8%), atypia or follicular lesion of undetermined significance in five (10.8%), suspicious for follicular neoplasm in five (10.8%), suspicious for malignant in three (6.5%), and malignant in 28 (60.1%) of the 46 nodules. Final histopathology was benign in 11 (24%) and DTC in 35 (76%), encompassing 34 PTC cases and one follicular thyroid carcinoma. Mean percentages of CD11b + HLA-DR low HIF1a + MDSC (CD11b + MDSC) were 14.0-6.2% and 7.9-3.6% in DTC versus benign nodules, respectively (p < 0.005). A cutoff of 12% yielded a specificity of 0.91, a sensitivity of 0.72, and a likelihood ratio of 7.9. Mean CD11b + MDSC levels increased linearly with higher TNM stage (p < 0.01), and were 19.4-5.4 in patients with persistent cancer after surgery compared with 13.2-6.8 in those without evidence of disease (p < 0.05). Conclusion: MDSC measurement using this flow cytometry-based assay represents a novel approach for pre-operatively assessing malignancy risk and cancer extent in patients with thyroid nodules. While further validation is needed, these data suggest that MDSC assessment may serve as a useful adjunct when cytology is indeterminate , and predict tumor stage and recurrence risk in cases of thyroid cancer.

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Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells

Cited by 94 publications

References 40 publications

Pten Null Prostate Epithelium Promotes Localized Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Tumor Initiation and Progression

Pten Null Prostate Epithelium Promotes Localized Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Tumor Initiation and Progression

Transforming growth factor-β signaling in tumor initiation, progression and therapy in breast cancer: an update

Circulating Myeloid-Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent

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