Single-Cell Transcriptome Analysis Reveals Neutrophil Populations in Gastric Cancer
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE168537 | GEO | 2023/09/11
REPOSITORIES: GEO
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Project description:Neutrophils accumulate in solid tumors and their abundance correlates with poor prognosis. Neutrophils are not homogenous, however, and could play different roles in cancer therapy. Here, we investigated the role of neutrophils in immunotherapy leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sell-hi state, rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of antitumor immunity, including BATF3-dependent DCs, IL12 and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy.
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Project description:Neutrophils accumulate in solid tumors and their abundance correlates with poor prognosis. Neutrophils are not homogenous, however, and could play different roles in cancer therapy. Here, we investigated the role of neutrophils in immunotherapy leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sell-hi state, rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of antitumor immunity, including BATF3-dependent DCs, IL12 and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy.
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Project description:Primary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow-derived cells. Here we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells in mouse models of breast cancer. Tumor-entrained neutrophils (TENs) inhibit metastatic seeding in the lungs by generating H2O2, and tumor-secreted CCL2 is a critical mediator of optimal anti-metastatic entrainment of G-CSF-stimulated neutrophils. TENs are present in the peripheral blood of breast cancer patients prior to surgical resection but not in healthy individuals. Thus, while tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site. This experiment was designed to compare the RNA expression profile in resting (control) neutrophils vs. that of TENs (neutrophils purified from tumor-bearing mice). In addition, we also compared the expression profiles of cultured neutrophils in vitro and treated with CCL2, CCL5 and GCSF.
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Project description:Single-Cell Transcriptome Analysis Reveals Neutrophil Populations in Gastric Cancer
| PRJNA708252 | ENA
Project description:Tumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. Several studies have shown that the presence of TGF-β in the tumor microenvironment contributes to the skewing of neutrophils to have a more pro-tumor phenotype. However, the direct effects of TGF-β on neutrophil signaling and migration are unclear. We sought to characterize TGF-β signaling in both primary human neutrophils and the neutrophil-like cell line HL-60 and determine whether TGF-β directly induces neutrophil migration. We found that TGF-β1 does not induce neutrophil migration in either a transwell or an underagarose migration assay. However, TGF-β1 does activate signals canonically through SMAD3 and noncanonically through ERK1/2 in neutrophils in a time and dose-dependent manner. Additionally, TGF-β1 present in the tumor-conditioned media (TCM) is responsible for SMAD3 activation. Moreover, we discovered that TCM from aggressive breast cancer cells induces neutrophils to secrete leukotriene B4 (LTB4), which is a lipid mediator important for amplifying neutrophil recruitment. However, we found that TGF-β1 alone does not induce secretion of LTB4. We next performed RNA-sequencing to evaluate the effects of TGF-β1 and TCM on the neutrophil transcriptome. We found that TGF-β1 and TCM result in changes in gene transcription in HL-60 cells, specifically of two pro-tumor genes OSM and VEGFA. Together, our findings characterize the effects of TGF-β1 on neutrophil signaling, migration, and gene expression that can be applied to understanding the changes in neutrophils that occur in the tumor microenvironment.
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Project description:Neutrophils are increasingly recognized as key players in the tumour immune response, and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined.Using Assay for Transposase Accessible Chromatin (ATAC) sequencing, we show that immature and mature neutrophils infiltrating the tumor share a similar chromatin accessibility profile that was not observed in non-tumor populations (in both tumor-bearing and wild type mice). Our results thus indicate that tumor-infiltrating neutrophils can be reprogrammed by the tumor microenvironment regardless of their stage of maturity by converging chromatin trajectories towards a distinct T3 state.
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Project description:The purpose of the present study was to elucidate the exocytic events in neutrophil-mediated inflammation. Therefore, we first investigated the expression of genes implicated in these exocytic events in a cell model for neutrophils, the promyelocytic HL-60 cell line. By the addition of 1.3% DMSO during 4.5 days, these cells are differentiated into neutrophil-like dHL-60 cells. Non-differentiated cells served as control. Upon cell differentiation, we i) identified differentially expressed genes implicated in the mechanisms of vesicle transport, and ii) found some of them being upregulated. This upregulated gene expression upon DMSO-maturation points towards a functional role in these cells. Secondly, we confirmed the expression of the selected genes in human neutrophils, isolated from venous blood of 4 different donors.
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