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Dive into the research topics where Colleen S. Netherby is active.

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Featured researches published by Colleen S. Netherby.


Journal of Clinical Investigation | 2013

Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis

Jeremy D. Waight; Colleen S. Netherby; Mary L. Hensen; Austin Miller; Qiang Hu; Song Liu; Paul N. Bogner; Matthew R. Farren; Kelvin P. Lee; Kebin Liu; Scott I. Abrams

Myeloid-derived suppressor cells (MDSCs) comprise immature myeloid populations produced in diverse pathologies, including neoplasia. Because MDSCs can impair antitumor immunity, these cells have emerged as a significant barrier to cancer therapy. Although much research has focused on how MDSCs promote tumor progression, it remains unclear how MDSCs develop and why the MDSC response is heavily granulocytic. Given that MDSCs are a manifestation of aberrant myelopoiesis, we hypothesized that MDSCs arise from perturbations in the regulation of interferon regulatory factor-8 (IRF-8), an integral transcriptional component of myeloid differentiation and lineage commitment. Overall, we demonstrated that (a) Irf8-deficient mice generated myeloid populations highly homologous to tumor-induced MDSCs with respect to phenotype, function, and gene expression profiles; (b) IRF-8 overexpression in mice attenuated MDSC accumulation and enhanced immunotherapeutic efficacy; (c) the MDSC-inducing factors G-CSF and GM-CSF facilitated IRF-8 downregulation via STAT3- and STAT5-dependent pathways; and (d) IRF-8 levels in MDSCs of breast cancer patients declined with increasing MDSC frequency, implicating IRF-8 as a negative regulator in human MDSC biology. Together, our results reveal a previously unrecognized role for IRF-8 expression in MDSC subset development, which may provide new avenues to target MDSCs in neoplasia.


Cancer Immunology, Immunotherapy | 2015

Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy

Michelle N. Messmer; Colleen S. Netherby; Debarati Banik; Scott I. Abrams

Immune function relies on an appropriate balance of the lymphoid and myeloid responses. In the case of neoplasia, this balance is readily perturbed by the dramatic expansion of immature or dysfunctional myeloid cells accompanied by a reciprocal decline in the quantity/quality of the lymphoid response. In this review, we seek to: (1) define the nature of the atypical myelopoiesis observed in cancer patients and the impact of this perturbation on clinical outcomes; (2) examine the potential mechanisms underlying these clinical manifestations; and (3) explore potential strategies to restore normal myeloid cell differentiation to improve activation of the host antitumor immune response. We posit that fundamental alterations in myeloid homeostasis triggered by the neoplastic process represent critical checkpoints that govern therapeutic efficacy, as well as offer novel cellular-based biomarkers for tracking changes in disease status or relapse.


Science Signaling | 2014

Tumor-Induced STAT3 Signaling in Myeloid Cells Impairs Dendritic Cell Generation by Decreasing PKCβII Abundance

Matthew R. Farren; Louise M. Carlson; Colleen S. Netherby; Inna Lindner; Pui-Kai Li; Dmitry I. Gabrilovich; Scott I. Abrams; Kelvin P. Lee

Tumor-derived factors repress immune responses by reducing protein kinase C signaling in dendritic cell progenitors. Preventing the Antitumor Immune Response Within the tumor microenvironment, tumor cells use many mechanisms to subvert the immune response, such as secreting factors that suppress the differentiation of myeloid progenitor cells into dendritic cells (DCs), which are critical for the activation of antitumor T cells. Farren et al. found that activation of signal transducer and activator of transcription 3 (STAT3) signaling in myeloid progenitor cells exposed to conditioned medium from breast cancer cells resulted in a decrease in the abundance of protein kinase C βII (PKCβII), which is required for their differentiation into DCs. PKCβII abundance in myeloid cells was decreased in patients with advanced breast cancer and in mouse models of breast cancer. STAT3 bound to the promoter of PRKCB (which encodes PKCβII), inhibiting its expression and the generation of DCs. Conversely, PKCβII signaling stimulated PRKCB expression, as well as reduced the cell surface abundance of STAT3-activating receptors. Identification of these dueling pathways suggests that therapies that enhance PKCβII signaling in myeloid progenitors may increase the effectiveness of STAT3-targeted therapies. A major mechanism by which cancers escape control by the immune system is by blocking the differentiation of myeloid cells into dendritic cells (DCs), immunostimulatory cells that activate antitumor T cells. Tumor-dependent activation of signal transducer and activator of transcription 3 (STAT3) signaling in myeloid progenitor cells is thought to cause this block in their differentiation. In addition, a signaling pathway through protein kinase C βII (PKCβII) is essential for the differentiation of myeloid cells into DCs. We found in humans and mice that breast cancer cells substantially decreased the abundance of PKCβII in myeloid progenitor cells through a mechanism involving the enhanced activation of STAT3 signaling by soluble, tumor-derived factors (TDFs). STAT3 bound to previously undescribed negative regulatory elements within the promoter of PRKCB, which encodes PKCβII. We also found a previously undescribed counter-regulatory mechanism through which the activity of PKCβII inhibited tumor-dependent STAT3 signaling by decreasing the abundance of cell surface receptors, such as cytokine and growth factor receptors, that are activated by TDFs. Together, these data suggest that a previously unrecognized cross-talk mechanism between the STAT3 and PKCβII signaling pathways provides the molecular basis for the tumor-induced blockade in the differentiation of myeloid cells, and suggest that enhancing PKCβII activity may be a therapeutic strategy to alleviate cancer-mediated suppression of the immune system.


Journal of Immunology | 2017

The Granulocyte Progenitor Stage Is a Key Target of IRF8-Mediated Regulation of Myeloid-Derived Suppressor Cell Production

Colleen S. Netherby; Michelle N. Messmer; Lauren Burkard-Mandel; Sean Colligan; Austin Miller; Eduardo Cortes Gomez; Jianmin Wang; Michael J. Nemeth; Scott I. Abrams

Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN). Intriguingly, the latter subset predominates in many patients and tumor models, although the mechanisms favoring PMN-MDSC responses remain poorly understood. Ordinarily, lineage-restricted transcription factors regulate myelopoiesis that collectively dictate cell fate. One integral player is IFN regulatory factor (IRF)–8, which promotes monocyte/dendritic cell differentiation while limiting granulocyte development. We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. However, where IRF8 acts in the pathway of myeloid differentiation to influence PMN-MDSC production has remained unknown. In this study, we showed that: 1) tumor growth was associated with a selective expansion of newly defined IRF8lo granulocyte progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8−/− GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8lo GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy.


Cancer Immunology, Immunotherapy | 2017

Mechanisms overseeing myeloid-derived suppressor cell production in neoplastic disease

Colleen S. Netherby; Scott I. Abrams

Perturbations in myeloid cell differentiation are common in neoplasia, culminating in immature populations known as myeloid-derived suppressor cells (MDSCs). MDSCs favor tumor progression due to their ability to suppress host immunity or promote invasion and metastasis. They are thought to originate from the bone marrow as a result of exposure to stromal- or circulating tumor-derived factors (TDFs). Although great interest has been placed on understanding how MDSCs function, less is known regarding how MDSCs develop at a transcriptional level. Our work explores the premise that MDSCs arise because cancer cells, through the production of certain TDFs, inhibit the expression of interferon regulatory factor-8 (IRF8) that is ordinarily essential for controlling fundamental properties of myeloid cell differentiation. Our interest in IRF8 has been based on the following rationale. First, it is well-recognized that IRF8 is a ‘master regulator’ of normal myelopoiesis, critical not only for producing monocytes, dendritic cells (DCs), and neutrophils, but also for controlling the balance of all three major myeloid cell types. This became quite evident in IRF8−/− mice, whereby the loss of IRF8 leads to a disproportionate accumulation of neutrophils at the expense of monocytes and DCs. Second, we showed that such myeloid populations from IRF8−/− mice exhibit similar characteristics to MDSCs from tumor-bearing mice. Third, in a reciprocal fashion, we showed that enforced expression of IRF8 in the myeloid system significantly mitigates tumor-induced MDSC accumulation and improves immunotherapy efficacy. Altogether, these observations support the hypothesis that IRF8 is an integral negative regulator of MDSC biology.


The Prostate | 2016

Generation of a C57BL/6 MYC-Driven Mouse Model and Cell Line of Prostate Cancer.

Leigh Ellis; Sheng Yu Ku; Qiuhui Li; Gissou Azabdaftari; Joseph Seliski; Brian M. Olson; Colleen S. Netherby; Dean G. Tang; Scott I. Abrams; David W. Goodrich; Roberto Pili

Transgenic mouse modeling is a favorable tool to reflect human prostate tumorigenesis and interactions between prostate cancer and the microenvironment. The use of GEMMs and derived cell lines represent powerful tools to study prostate cancer initiation and progression with an associated tumor microenvironment. Notably, such models provide the capacity for rapid preclinical therapy studies including immune therapies for prostate cancer treatment.


Cancer Research | 2016

Abstract 3249: Regulation of interferon regulatory factor-8 (IRF8) during myelopoiesis is a critical checkpoint for the formation of defective myeloid cells in cancer

Colleen S. Netherby; Michelle N. Messmer; Scott I. Abrams

Aberrant myelopoiesis is commonly observed in patients with solid cancers. This results in the production of myeloid-derived suppressive cells (MDSCs) which promote tumor growth and metastasis. However, the molecular mechanisms underlying MDSC development have remained poorly understood. The transcription factor IRF8 is integral for overseeing myelopoietic fate; high IRF8 expression during normal myelopoiesis favors monocytic differentiation and directly inhibits granulocytic differentiation. We recently showed that tumor-derived STAT3/5-activating cytokines downregulate the expression of IRF8 in myeloid cells leading to the accumulation of MDSCs in the periphery, which are primarily granulocytic. However it is unclear if MDSC production is a consequence of IRF8 downregulation in the periphery or upstream in the bone marrow during myelopoiesis. To that end, we utilized a novel mouse model expressing an IRF8-EGFP fusion protein which allowed us to investigate changes in IRF8 expression during both orthotopic and spontaneous mammary tumor growth and progression. Our results showed that: 1) the total granulocyte-monocyte progenitor (GMP) fraction, as with the peripheral MDSC population, was responsive to tumor burden and greatly expanded with increasing tumor size, and 2) IRF8 expression within the total GMPs significantly decreased during tumor growth, reflecting the expansion of a newly defined primarily IRF8lo granulocyte progenitor (GP) population, and 3) tumor-induced GPs were hyper-responsive not only to G-CSF, but also M-CSF to generate a ‘biased’ granulocytic MDSC-like phenotype. Expression of IRF8 in other progenitor populations was not affected, suggesting that IRF8lo GMPs/GPs are a key source of the peripheral MDSC response. Lastly, genetically enforced IRF8 expression in myeloid progenitors of the bone marrow constrained aberrant myelopoiesis during tumor growth, resulting in delayed autochthonous tumor growth and reduced spontaneous lung metastasis. Altogether, these data reinforce the notion that modulation of IRF8 in myeloid progenitors is an early consequence of the neoplastic process and a potential target for therapeutic intervention. NIH R01CA140622 NIH T32CA085183 Citation Format: Colleen S. Netherby, Michelle N. Messmer, Scott I. Abrams. Regulation of interferon regulatory factor-8 (IRF8) during myelopoiesis is a critical checkpoint for the formation of defective myeloid cells in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3249.


Journal of Interferon and Cytokine Research | 2016

Relevance of Interferon Regulatory Factor-8 Expression in Myeloid-Tumor Interactions.

Scott I. Abrams; Colleen S. Netherby; Danielle Y. F. Twum; Michelle N. Messmer


Oncotarget | 2015

MMP3-mediated tumor progression is controlled transcriptionally by a novel IRF8-MMP3 interaction

Debarati Banik; Colleen S. Netherby; Paul N. Bogner; Scott I. Abrams


Archive | 2018

Unique Challenges Facing Immunotherapy of Metastatic Ovarian Cancer

Michelle N. Messmer; Colleen S. Netherby; Scott I. Abrams

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Scott I. Abrams

Roswell Park Cancer Institute

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Michelle N. Messmer

Roswell Park Cancer Institute

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Austin Miller

Roswell Park Cancer Institute

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Paul N. Bogner

Roswell Park Cancer Institute

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Debarati Banik

Roswell Park Cancer Institute

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Jeremy D. Waight

Roswell Park Cancer Institute

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Kebin Liu

Georgia Regents University

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Kelvin P. Lee

Roswell Park Cancer Institute

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Matthew R. Farren

Roswell Park Cancer Institute

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Brian M. Olson

University of Wisconsin-Madison

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