Deconvolution of myeloid cell cytokine specific transcriptional profiles during tuberculosis and cancer identifies neutrophil activation as a prognostic feature
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145648 | GEO | 2020/02/21
REPOSITORIES: GEO
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Project description:The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could guide therapy or predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils to stimulation by type 1 cytokines (IFN-g, IFN-b and IFN-l) type 2 cytokines (IL-4 and IL-13) and the immunoregulatory cytokine IL-10. This generated a myeloid cell cytokine specific response matrix to infer representation of myeloid cells and the cytokine environment they may encounter during infection and in tumors. Neutrophils were surprisingly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-b stimulation, whereas other IFN signature genes were upregulated by both IFN-g and IFN-b. When used to deconvolute blood profiles from tuberculosis patients, the IFN-b specific neutrophil signature was surprisingly reduced in TB patients with active disease whereas the shared response to IFN-g and IFN-b in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-g or IFN-b emerged as opposing predictors of survival in samples from patients with glioma. This approach may help delineate biological roles for myeloid cells in different cytokine environments during disease processes.
2020-02-21 | GSE145647 | GEO
Project description:The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could guide therapy or predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils to stimulation by type 1 cytokines (IFN-g, IFN-b and IFN-l) type 2 cytokines (IL-4 and IL-13) and the immunoregulatory cytokine IL-10. This generated a myeloid cell cytokine specific response matrix to infer representation of myeloid cells and the cytokine environment they may encounter during infection and in tumors. Neutrophils were surprisingly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-b stimulation, whereas other IFN signature genes were upregulated by both IFN-g and IFN-b. When used to deconvolute blood profiles from tuberculosis patients, the IFN-b specific neutrophil signature was surprisingly reduced in TB patients with active disease whereas the shared response to IFN-g and IFN-b in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-g or IFN-b emerged as opposing predictors of survival in samples from patients with glioma. This approach may help delineate biological roles for myeloid cells in different cytokine environments during disease processes.
2019-10-01 | GSE131990 | GEO
Project description:Myeloid cells are a vital component of innate immunity and comprise monocytes, macrophages, dendritic cells, and granulocytes. How myeloid cell lineage affects activation states in response to cytokines remains poorly understood. The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that predict disease outcome. In this study, we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells, and neutrophils in response to stimulation by IFN-γ, IFN-β, IFN-λ, IL-4, IL-13, and IL-10 cytokines to better understand the heterogeneity of activation states in inflammatory conditions. This generated a myeloid cell-cytokine-specific response matrix that can infer representation of myeloid cells and the cytokine environment they encounter during infection, in tumors and in whole blood. Neutrophils were highly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-β stimulation, whereas other IFN signature genes were upregulated by both IFN-γ and IFN-β. When we used our matrix to deconvolute blood profiles from tuberculosis patients, the IFN-β-specific neutrophil signature was reduced in tuberculosis patients with active disease, whereas the shared response to IFN-γ and IFN-β in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4/IL-13 and monocyte responses to IFN-γ or IFN-β emerged as opposing predictors of patient survival. Hence, by dissecting how different myeloid cells respond to cytokine activation, we can delineate biological roles for myeloid cells in different cytokine environments during disease processes, especially during infection and tumor progression.
| S-EPMC7276940 | biostudies-literature
Project description:Deconvolution of myeloid cell cytokine specific transcriptional profiles during tuberculosis and cancer identifies neutrophil activation as a prognostic feature
| PRJNA607795 | ENA
Project description:Deconvolution of myeloid cell cytokine specific transcriptional profiles during tuberculosis and cancer identifies neutrophil activation as a prognostic feature [whole blood]
| PRJNA607797 | ENA
Project description:Deconvolution of myeloid cell cytokine specific transcriptional profiles during tuberculosis and cancer identifies neutrophil activation as a prognostic feature [cultured cells]
| PRJNA545516 | ENA
Project description:Acute myeloid leukemia (AML) is one of the malignant hematologic cancers with rapid progress and poor prognosis. Most AML prognostic stratifications focused on genetic abnormalities. However, none of them was established based on the cell type compositions (CTCs) of peripheral blood or bone marrow aspirates from patients at diagnosis. Here we sought to develop a novel prognostic model for AML in adults based on the CTCs. First, we applied the CIBERSORT algorithm to estimate the CTCs for patients from two public datasets (GSE6891 and TCGA-LAML) using a custom gene expression signature reference constructed by an AML single-cell RNA sequencing dataset (GSE116256). Then, a CTC-based prognostic model was established using least absolute shrinkage and selection operator Cox regression, termed CTC score. The constructed prognostic model CTC score comprised 3 cell types, GMP-like, HSC-like, and T. Compared with the low-CTC-score group, the high-CTC-score group showed a 1.57-fold [95% confidence interval (CI), 1.23 to 2.00; p = 0.0002] and a 2.32-fold (95% CI, 1.53 to 3.51; p < 0.0001) higher overall mortality risk in the training set (GSE6891) and validation set (TCGA-LAML), respectively. When adjusting for age at diagnosis, cytogenetic risk, and karyotype, the CTC score remained statistically significant in both the training set [hazard ratio (HR) = 2.25; 95% CI, 1.20 to 4.24; p = 0.0119] and the validation set (HR = 7.97; 95% CI, 2.95 to 21.56; p < 0.0001]. We further compared the performance of the CTC score with two gene expression-based prognostic scores: the 17-gene leukemic stem cell score (LSC17 score) and the AML prognostic score (APS). It turned out that the CTC score achieved comparable performance at 1-, 2-, 3-, and 5-years timepoints and provided independent and additional prognostic information different from the LSC17 score and APS. In conclusion, the CTC score could serve as a powerful prognostic marker for AML and has great potential to assist clinicians to formulate individualized treatment plans.
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Project description:Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with a complex spectrum of cellular and molecular characteristics including several dramatic changes in the populations of peripheral leukocytes. These changes include general leukopenia, activation of B and T cells, and maturation of granulocytes. The manifestation of SLE in peripheral blood is central to the disease but is incompletely understood. A technique for rigorously characterizing changes in mixed populations of cells, microarray expression deconvolution, has been applied to several areas of biology but not to SLE or to blood. Here we demonstrate that microarray expression deconvolution accurately quantifies the constituents of real blood samples and mixtures of immune-derived cell lines. We characterize a broad spectrum of peripheral leukocyte cell types and states in SLE to uncover novel patterns including: specific activation of NK and T helper lymphocytes, relationships of these patterns to each other, and correlations to clinical variables and measures. The expansion and activation of monocytes, NK cells, and T helper cells in SLE at least partly underlie this disease's prominent interferon signature. These and other patterns of leukocyte dynamics uncovered here correlate with disease severity and treatment, suggest potential new treatments, and extend our understanding of lupus pathology as a complex autoimmune disease involving many arms of the immune system.
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Project description:High circulating neutrophil-lymphocyte ratio (NLR) appears to be prognostic in metastatic colorectal cancer (mCRC). We investigated the relationship of NLR with circulating cytokines and molecular alterations.We performed retrospective analyses on multiple cohorts of CRC patients (metastatic untreated (n=166), refractory metastatic (n=161), hepatectomy (n=198), stage 2/3 (n=274), and molecularly screened (n=342)). High NLR (ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood) was defined as NLR>5. Plasma cytokines were evaluated using multiplex-bead assays. Kaplan-Meier estimates, non-parametric correlation analysis, and hierarchical cluster analyses were used.High NLR was associated with poor prognosis in mCRC (hazard ratio (HR) 1.73; 95% confidence interval (CI):1.03-2.89; P=0.039) independent of known prognostic factors and molecular alterations (KRAS/NRAS/BRAF/PIK3CA/CIMP). High NLR correlated with increased expression of interleukin 6 (IL-6), IL-8, IL-2R?, hepatocyte growth factor, macrophage-colony stimulating factor, and vascular epidermal growth factor in exploratory (n=39) and validation (n=166) cohorts. Fourteen additional cytokines correlated with high NLR in the validation cohort. All 20 cytokines fell into three major clusters: inflammatory cytokines, angiogenic cytokines, and epidermal growth factor ligands. In mCRC, composite stratification based on NLR-cytokine score provided enhanced prognostic information (HR 2.09; 95% CI: 1.59-2.76; P<0.001) over and above NLR.High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis. A composite NLR-cytokine stratification has enhanced prognostic value in mCRC.
| S-EPMC4366901 | biostudies-other
Project description:HIV infection is a significant risk factor for reactivation of latent Mycobacterium tuberculosis infection (LTBI) and progression to active tuberculosis disease, yet the mechanisms whereby HIV impairs T cell immunity to M. tuberculosis have not been fully defined. Evaluation of M. tuberculosis-specific CD4 T cells is commonly based on IFN-γ production, yet increasing evidence indicates the immune response to M. tuberculosis is heterogeneous and encompasses IFN-γ-independent responses. We hypothesized that upregulation of surface activation-induced markers (AIM) would facilitate detection of human M. tuberculosis-specific CD4 T cells in a cytokine-independent manner in HIV-infected and HIV-uninfected individuals with LTBI. PBMCs from HIV-infected and HIV-uninfected adults in Kenya were stimulated with CFP-10 and ESAT-6 peptides and evaluated by flow cytometry for upregulation of the activation markers CD25, OX40, CD69, and CD40L. Although M. tuberculosis-specific IFN-γ and IL-2 production was dampened in HIV-infected individuals, M. tuberculosis-specific CD25+OX40+ and CD69+CD40L+ CD4 T cells were detectable in the AIM assay in both HIV-uninfected and HIV-infected individuals with LTBI. Importantly, the frequency of M. tuberculosis-specific AIM+ CD4 T cells was not directly impacted by HIV viral load or CD4 count, thus demonstrating the feasibility of AIM assays for analysis of M. tuberculosis-specific CD4 T cells across a spectrum of HIV infection states. These data indicate that AIM assays enable identification of M. tuberculosis-specific CD4 T cells in a cytokine-independent manner in HIV-uninfected and HIV-infected individuals with LTBI in a high-tuberculosis burden setting, thus facilitating studies to define novel T cell correlates of protection to M. tuberculosis and elucidate mechanisms of HIV-associated dysregulation of antimycobacterial immunity.
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