Stroma-derived Dickkopf-1 suppresses NK cell cytotoxicity in breast cancer
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PROVIDER: PRJNA1093077 | ENA |
REPOSITORIES: ENA
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Project description:Effects of DKK1 on tumor cells and NK cells
2024-04-11 | GSE262733 | GEO
Project description:Background Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Methods A proteome profiler array was performed to identify secreted CXCL16 protein, the expression of which is regulated by ELK3 to control natural killer (NK) cell-mediated cytotoxicity. The correlation between ELK3 and CXCL16 was investigated by microarray and TCGA data analysis. NK cell cytotoxicity and migration assays were performed to examine the role of ELK3-CXCL16 in regulating the anticancer effect in TNBC. CXCL16-mediated NK cell recruitment and NK cell cytotoxicity were examined in an experimental metastasis mouse model and in an MDA-MB231 orthotopic mouse model. Results We show that targeting the ETS transcription factor ELK3 recruits immune cells including NK cells into tumors via the chemotactic activity of the chemokine. ELK3 depletion upregulated CXCL16 expression, thereby inducing NK cell recruitment to tumors and increasing NK cell cytotoxicity in TNBC . In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Conclusions The ELK3-CXCL16 axis regulates NK cell recruitment and increases NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.
2022-07-20 | GSE208584 | GEO
Project description:STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing Stat1-Y701F. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1-/- animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo suggesting a so-far unknown cytoplasmic function. Using immunofluorescence technology we uncovered the recruitment of STAT1 to the immunological synapse during NK cell killing. A Stat1ind mouse expressing FLAG-tagged STAT1α was used to study the STAT1α interactome in NK cells. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. We propose a novel function for STAT1 in the immunological synapse of NK cells regulating tumor surveillance and cytotoxicity.
2016-10-07 | PXD002206 | Pride
Project description:Cancer associated fibroblasts (CAFs) are one of the most abundant components of the breast tumor microenvironment (TME) and major contributors to immune modulation in the TME. CAFs are well known to regulate the activity of diverse types of immune cells including T cells, macrophages and dendritic cells, however little is known about their interaction with Natural killer (NK) cells. NK cells constitute an important arm of anti-tumor immunity, yet the regulation of NK cell activity by CAFs in solid tumors is poorly understood. Here we find, using mouse models of cancer and ex-vivo cocultures, that immunosuppressive CAF subsets severely inhibit NK cell cytotoxicity towards cancer cells. We unravel the mechanism by which this suppression occurs, through CAF-mediated downregulation of the NK-surface receptors, Natural Killer Group 2D (NKG2D) and DNAX Accessory Molecule-1 (DNAM-1). Ligands for these receptors are known to be expressed by cancer cells and minimally expressed in healthy tissue. Here we find that CAFs also upregulate ligands for NKG2D and DNAM-1. Ligand-receptor engagement between NK cells and CAFs leads to CAF cytolysis, which in turn diminishes the expression of NKG2D and DNAM-1 on NK cells via a negative feedback loop, and promotes cancer escape from NK cell surveillance. These results reveal a CAF-mediated immunosuppressive mechanism with implications for treatment of solid tumors.
2023-11-14 | GSE247218 | GEO
Project description:A key mechanism of tumor resistance to immune cells is mediated by expression of peptide-loaded HLA-E in tumor cells, which suppresses natural killer (NK) cell activity via ligation of the NK inhibitory receptor CD94/NKG2A. To bypass HLA-E inhibition, we developed a way to generate highly functional NK cells lacking NKG2A. Constructs containing a single-chain variable fragment derived from an anti-NKG2A antibody were linked to endoplasmic reticulum-retention domains. After retroviral transduction in human peripheral blood NK cells, these NKG2A Protein Expression Blockers (PEBLs) abrogated NKG2A expression. The resulting NKG2Anull NK cells had higher cytotoxicity against HLA-E-expressing tumor cells.
2019-05-17 | GSE127081 | GEO
Project description:Natural killer (NK) cells exhibit anti-fibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cell (HSC) populations. Prostaglandin (PG) E2 plays a dual role in innate and adaptive immunity. E-prostanoid 3 receptor (EP3) was markedly downregulated in NK cells from liver fibrosis mice and patients with liver cirrhosis. NK cell-specific deletion of EP3 aggravated hepatic fibrogenesis in mouse models of LF. For an in-depth analysis of the molecular alterations mediated by EP3 in NK cells, single-cell RNA sequencing (scRNA-seq) was performed using CD27+CD11b+ NK cells. GO, KEGG, GSEA revealed that the adhesion signaling pathway was downregulated in EP3-deficient NK cells. This phenotype was confirmed by qRT-PCR and function experiments. Thus, EP3 is required for adhesion and cytotoxicity of NK cells toward HSCs and may serve as a therapeutic target for the management of LF.
2022-02-19 | GSE196864 | GEO
Project description:Aire suppresses CTLA-4 expression from thymic stroma to control autoimmunity
| PRJNA648393 | ENA
Project description:NK cells may acquire under certain conditions features of adaptive immune cells. As the functional role of memory NK cells in cancer has so far remained elusive, we reasoned whether tumor-priming itself might promote memory NK cell generation. We provide substantial evidence that independent from pro-inflammatory stimulation, tumor-induced memory-like (TIML) NK cells exhibit a heightened, tumor-restricted cytotoxicity which is dependent on a higher/faster perforin but not IFN-γ release. Comparative transcriptome analysis reveals that gene expression patterns differ between TIML- and Cytokine-induced memory-like (CIML)-NK cells.
2016-04-15 | E-MTAB-4606 | biostudies-arrayexpress
Project description:Dickkopf 1 (DKK1) could promote tumor progression by suppressing immunity. Therefore, we investigated whether DKK1 influence prognosis and sensitivity to PD-1 blockade in colorectal cancers (CRCs) with defective DNA mismatch repair genes (dMMR) or microsatellite instability (MSI). We found that elevated DKK1 expression was associated with recurrence and dismissed CD8+ T cell infiltrations, and patients with high serum DKK1 had poor anti-PD-1 response. RNA interference or neutralization of DKK1 in CRCs enhanced CD8+ T cell cytotoxicity, and down-regulation of T-bet and E2F1 following GSK3β activation was detected in DKK1-treated CD8+ T cells. In organoid-lymphocyte co-culture model, apoptosis proportions were elevated after individual neutralization of both PD-1 and DKK1, and the combined neutralization resulted in further increases. In conclusion, DKK1 suppresses tumor immunity in dMMR/MSI CRCs by inactivating CD8+ T cells through GSK3β/E2F1/T-bet axis. DKK1 neutralization may improve the sensitivity to PD-1 blockade in dMMR/MSI CRCs.
2021-04-07 | GSE149206 | GEO
Project description:Resistance of tumor cells to cell-mediated cytotoxicity remains a drawback in the immunotherapy of cancer and its molecular basis is poorly understood. To investigate the acquisition of tumor resistance to cell-mediated cytotoxicity, resistant variants were selected following long term NK cell selection pressure. We found that these variants are resistant to NK cell-mediated lysis but still sensitive to autologous cytotoxic T lymphocytes or cytotoxic drugs. This resistance seems to be dependent, at least partly, of an alteration of the target cell recognition by NK effector cells, but does not appear to involve any alteration of KIR, DNAM1 or NKG2D ligands expression on resistant cells nor the induction of a protective autophagy. To gain further insight into the molecular mechanisms underlying the acquired tumor resistance to NK cells-mediated cytotoxicity, we have conducted a comprehensive analysis of the variants transcriptome. Comparative analysis identified an expression profile of genes that best distinguished resistant variant from parental sensitive cancer cells with candidate genes putatively involved in NK cell-mediated lysis resistance, but also in adhesion, migration and invasiveness including up-regulated genes such as POT1, L1CAM or ECM1 and down-regulated genes like B7-H6 or UCHL1. Consequently, the selected variants did not only display resistance to NK cell-mediated lysis but also exhibited more aggressive properties. The present studies emphasize that NK cells expand far beyond the simple killing of malignant cells and may be important effectors during cancer immunoediting.This study aims to compare transcriptome of T1_ref cells (2 triplicates samples untreated versus 2 triplicate samples of T1 after cocultured with NK cells).
2020-11-02 | E-MTAB-8777 | biostudies-arrayexpress