Triple-Negative Breast Cancer Shapes the Systemic Immune Landscape and Alters Neutrophil Functionality [bulkRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1101001 | ENA |
REPOSITORIES: ENA
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Project description:Cancer dysregulates intratumoral innate-adaptive immune cell crosstalk, but it remains largely unknown how the systemic immune landscape is modified during breast cancer progression. Here, we comprehensively profiled the circulating immune profile of patients with stage I-III or stage IV triple-negative breast cancer (TNBC) and healthy donors (HDs). We showed that patients with metastatic TNBC (mTNBC) exhibited decreased numbers of circulating T cells, dendritic cell subsets and differentiated B cells compared to patients with stage I-III TNBC and HDs, which was partially associated with prior chemotherapy. Moreover, increased IL17 production by vδ1 γδ T cells was observed in patients with mTNBC compared to HDs. Classical monocytes and neutrophils were increased in patients with mTNBC compared to HDs, irrespective of prior chemotherapy. Transcriptional and proteomic analysis, alongside ex vivo functionality assays, revealed increased migratory capacity, increased abundance of granule proteins, and elevated ROS production in circulating neutrophils from mTNBC patients. Some of these systemic immune alterations, including decreased levels of non-switched B cells and increased migratory capacity of neutrophils, were already evident in patients with stage I-III TNBC. Our data underscore the significant impact of TNBC disease stage on the systemic immune composition and function.
2025-01-25 | GSE264108 | GEO
Project description:Little is known about how commensal colonization controls neutrophil differentiation and functions. Using system immunology approaches we discovered commensal and infection induced changes in neutrophil proteomes. The identified differentially expressed genes were CRISPRed out in immortalized neutrophil progenitor cell lines transduced with lenti-guides. Analysis of maturation and bactericidal capacity of the generated CRISPRed clones ascribed a function to a currently unknown protein-termed Prenylcysteine oxidase 1 like (Pcyox1l). Pcyox1l deficient neutrophils show dramatic defects in longevity, autophagy, and bactericidal functions associated with reductions in SerpinB1a transcripts and protein. Metabolic labeling experiments revealed that Pcyox1l controls levels of protein prenylation, highlighting its key enzymatic function. The Pcyox1l deficiency phenotype is phenocopied by SerpinB1a deficiency in neutrophils signifying linked mechanisms. Commensal colonization increases Pcyox1l and SerpinB1a levels in polymorphonuclear leukocytes (PMNs) in specific pathogen free (SPF) mice when compared to germ free (GF) mice and, conversely, Pcyox1l KO mice demonstrated altered commensal microbiome and elevated susceptibility to bacterial infection. Cumulatively, our data highlight a novel metabolic pathway which is controlled by commensal colonization and governs neutrophil functionality, longevity, and bactericidal properties. In lieu with the impairment of neutrophil bactericidal functions, Pcyox1l KO mice showed elevated susceptibility to infection with the Gram-negative pathogen Pseudomonas aeruginosa
2023-03-04 | PXD030922 | Pride
Project description:Sex differences in neutrophil biology modulate response to type I Interferons and immunometabolism (bulkRNA-seq)
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Project description:Systemic juvenile idiopathic arthritis (SJIA) is a chronic childhood arthropathy with features of autoinflammation. Early inflammatory SJIA is associated with expansion and activation of neutrophils with a sepsis-like phenotype, but neutrophil phenotypes present in longstanding and clinically inactive disease (CID) are unknown. The objective of this study was to examine activated neutrophil subsets, S100 alarmin release, and gene expression signatures in children with a spectrum of SJIA disease activity. Methods: Highly-purified neutrophils were isolated using a two-step procedure of density-gradient centrifugation followed by magnetic-bead based negative selection prior to flow cytometry or cell culture to quantify S100 protein release. Whole transcriptome gene expression profiles were compared in neutrophils from children with both active SJIA and CID. Results: Patients with SJIA and active systemic features demonstrated a higher number of CD16+CD62Llo neutrophil population compared to controls. This neutrophil subset was not seen in patients with CID or patients with active arthritis not exhibiting systemic features. Using imaging flow cytometry, CD16+CD62Llo neutrophils from patients with active SJIA and features of macrophage activation syndrome (MAS) had increased nuclear hypersegmentation compared to CD16+CD62L+ neutrophils. Serum levels of S100A8/A9 and S100A12 were strongly correlated with peripheral blood neutrophil counts. Neutrophils from active SJIA patients did not show enhanced resting S100 protein release; however, regardless of disease activity, neutrophils from SJIA patients did show enhanced S100A8/A9 release upon PMA stimulation compared to control neutrophils. Furthermore, whole transcriptome analysis of highly purified neutrophils from children with active SJIA identified 214 differentially expressed genes compared to neutrophils from healthy controls. The most significantly upregulated gene pathway was Immune System Process, including AIM2, IL18RAP, and NLRC4. Interestingly, this gene set showed intermediate levels of expression in neutrophils from patients with long-standing CID yet persistent serum IL-18 elevation. Indeed, all patient samples regardless of disease activity demonstrated elevated inflammatory gene expression, including inflammasome components and S100A8. Conclusion: We identify features of neutrophil activation in SJIA patients with active disease and CID, including a proinflammatory gene expression signature, reflecting persistent innate immune activation. Taken together, these studies expand understanding of neutrophil function in chronic autoinflammatory disorders such as SJIA.
2018-11-15 | GSE122552 | GEO
Project description:Interventions: monocyte/neutrophil apheresis
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Project description:Differences in female and male immunity may contribute to variations in response to infections and predisposition to autoimmunity. The characterization of the mechanisms that drive differential neutrophil phenotypes between genders has been investigated. This provides new insights that distinct sex difference in neutrophil biology related to responses to type I IFNs, immunometabolism and maturation status that may have prominent functional and pathogenic implications. The transcriptome of neutrophils from healthy adult males and females was characterized using bulk RNASeq. The transcriptome of whole blood leukocytes was elucidated using scRNASeq.
2020-06-29 | GSE145229 | GEO
Project description:Interventions: multiple monocyte/neutrophil apheresis
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Primary outcome(s): Evaluation neutrophil function of patients at high risk for postoperative infection treated with monocyte/neutrophil apheresis
Study Design: Parallel Non-randomized
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Project description:This SuperSeries is composed of the following subset Series: GSE39108: UNG shapes the specifity of AID-induced somatic hypermutation in non B cells GSE39114: UNG shapes the specifity of AID-induced somatic hypermutation in B cells Refer to individual Series
2012-07-04 | E-GEOD-39115 | biostudies-arrayexpress
Project description:The full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Here we profiled more than 25,000 mouse differentiating and mature neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function, and fate decision in their steady state and during bacterial infection. Eight neutrophil populations (including the GMP population) were defined by distinct molecular signatures, including a new circulating mature neutrophil population highly expressing interferon-stimulated genes. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets, a novel mechanism that highlights the complex and precise regulation of neutrophil production. Neutrophil heterogeneity and differentiation are driven by both known and uncharacterized transcription factors. Neutrophils gradually acquire microbicidal capability as cells traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil population, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall heterogeneity. Bacterial infection-induced emergency granulopoiesis is mediated by augmented proliferation of early-stage neutrophil progenitors and accelerated post-mitotic maturation. In summary, single-cell transcriptomics enabled the reconstruction of neutrophil differentiation and maturation trajectories and uncovered neutrophil subpopulations, gene pathways, and regulators of neutrophil function and fate decisions. These data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers, and therapeutic targets at single-cell resolution.
2020-05-27 | GSE137539 | GEO
Project description:Neutrophil gene expression in systemic juvenile idiopathic arthritis
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