FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE173569 | GEO | 2021/04/30
REPOSITORIES: GEO
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Project description:Neutrophil gene transcription following lipopolysaccharide exposure. Microarray analysis of lipopolysaccharide-treated human neutrophils. Neutrophils respond to infection by degranulation, release of reactive oxygen intermediates, and secretion of chemokines and cytokines; however, activation of neutrophil transcriptional machinery has been little appreciated. Recent findings suggest that gene expression may represent an additional neutrophil function after exposure to lipopolysaccharide (LPS). We performed microarray gene expression analysis of 4,608 mostly nonredundant genes on LPS-stimulated human neutrophils. Analysis of three donors indicated some variability but also a high degree of reproducibility in gene expression. Twenty-eight verifiable, distinct genes were induced by 4 h of LPS treatment, and 13 genes were repressed. Genes other than cytokines and chemokines are regulated; interestingly, genes involved in cell growth regulation and survival, transcriptional regulation, and interferon response are among those induced, whereas genes involved in cytoskeletal regulation are predominantly repressed. In addition, we identified monocyte chemoattractant protein-1 as a novel LPS-regulated chemokine in neutrophils. Included in these lists are five clones with no defined function. These data suggest molecular mechanisms by which neutrophils respond to infection and indicate that the transcriptional potential of neutrophils is greater than previously thought.
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Project description:BACKGROUND: Neutrophils are phagocytic innate immune cells that play essential roles in host defence, but are also implicated in inflammatory diseases such as rheumatoid arthritis (RA) where they contribute to systemic inflammation and joint damage. Transcriptomic analysis of neutrophils has revealed significant changes in gene expression in neutrophils activated in vitro by cytokines and in vivo during inflammation in RA. However, there are no reports on the global metabolomic changes that occur during neutrophil activation. The aim of this study was to establish protocols for the study changes in the metabolome of human neutrophils using 1H NMR spectroscopy.
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Project description:Despite the cancer treatment revolution brought on by the rapid advancement of immunotherapies, only a small fraction of patients derive clinical benefit. Moreover, eradication of large established tumors requires a concerted effort of complete immune system and hence identifying agents that activate and interlink both innate and adaptive immune system components is required. Here, we report that IL-36 cytokine can remodel an immune-suppressive tumor microenvironment (TME) and mediate potent anti-tumor immune response through hematopoietic cells, via both innate and adaptive immunity. Further, we demonstrate that IL-36 signaling reprograms neutrophils in a cell-intrinsic manner to greatly enhances their ability to directly kill tumor cells, their antigen presentation capability and promote T cell proliferation. Thus, the pleotropic effects of IL-36 transform neutrophils into potent effector cells to promote tumor rejection. While poor prognostic outcomes are associated with neutrophil enhancement in the TME, our results highlight the therapeutic potential of harnessing the ability of IL-36 signaling to reprogram neutrophils and link innate and adaptive immune system to enhance durable anti-tumor responses in solid tumors.
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Project description:An expansion of neutrophils often marks cancer. To date, neutrophils are assumed to be a relatively homogenous population, but recent studies describe both pro- and anti-tumor functions in neutrophils. This suggests there is more heterogeneity in neutrophils than previously appreciated. To better understand and target neutrophil functions in cancer, we must dissect neutrophil heterogeneity and how it changes from health to disease. To this end, we employed single-cell transcriptome technology to profile immature neutrophils from bone marrow of healthy individuals. Intriguingly, we identified a new neutrophil subset that expresses several B cell markers, including CD79a/b, components of the B cell receptors and PAX5, a lineage-specific transcriptional factor. We termed this population the BNeut. Using flow cytometry, we found that BNeuts are confined to the bone marrow of healthy individuals but expand into the blood of melanoma patients at an early stage, suggesting BNeuts might be a biomarker for disease. Additionally, we find BNeuts in the mouse models of different cancer types, including breast and lung carcinoma. The BNeut appears and functions more similar to a neutrophil than a B cell. BNeuts possess a neutrophil-like transcriptional profile, large cytoplasm with segmented nucleus, and produce ROS and NETs. Using imaging, we show that the BNeuts are single cells co-expressing both CD66b and CD79b, and lack the B cell surface marker CD19. To understand why neutrophils might use a B cell program, we explored different B cell functions including antigen presentation, a function that is usually absent from neutrophils. We show BNeuts are excellent at phagocytosis, including uptake of tumor cells. Further, BNeuts have increased expression of antigen presentation-related genes compared to other neutrophils and can modulate CD4+ T cell responses. Together, we have identified a novel neutrophil subset expressing B cell markers that is preferentially expanded in the blood of melanoma patients and poised to control T cell responses during disease.
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Project description:G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. We developed a neutralizing monoclonal antibody to the murine G-CSF receptor (G-CSFR), which antagonizes binding of murine G-CSF and inhibits G-CSFR signalling. Anti-G-CSFR rapidly halts the progression of established disease in collagen antibody-induced arthritis (CAbIA). Neutrophil accumulation in joints is inhibited, without rendering animals neutropenic, suggesting an effect on homing to inflammatory sites. Neutrophils in the blood and arthritic joints of anti-G-CSFR treated mice show alterations in cell adhesion receptors, while anti-G-CSFR suppresses local production of proinflammatory cytokines and chemokines known to drive tissue damage. Our aim in this study was to use differential gene expression analysis of joint and blood neutrophils to more thoroughly understand the effect of G-CSFR blockade on the inflammatory response following anti-G-CSFR therapy in CAbIA.
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