T cell impact rituximab-mediated NK cell transcriptomics
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE164086 | GEO | 2021/07/13
REPOSITORIES: GEO
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Project description:T cell impact rituximab-mediated NK cell transcriptomics
| PRJNA688891 | ENA
Project description:SUMOylation is a reversible post-translational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of Type I interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor TAK-981 in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and NK cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pre-treatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20-positive target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated synergistic antitumor activity of TAK-981 and rituximab in CD20-positive lymphoma xenograft models. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with lymphomas and solid tumors.
2024-04-24 | GSE185841 | GEO
Project description:Purpose: Despite recent advances in the treatment of patients with aggressive lymphomas, still a significant fraction of patients will succumb to their disease. Thus, novel therapeutic strategies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects. Experimental Design: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Results: Overall, three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 2/11 cell lines were primarily sensitive to tafasitamab and 2/11 were predominantly sensitive to rituximab treatment, the combination of tafasitamab and rituximab resulted in enhanced cell death in 7/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combinatorial approach of the two antibodies resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. Conclusions: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to antibody mono treatment in models of aggressive B-cell lymphoma in vitro and in vivo. Translational Relevance: The immunochemotherapy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains the standard of care for newly diagnosed DLBCL patients. However, 30-40% of patients are refractory or relapse after initial response to the immunochemotherapy, indicating a high-unmet medical need for these patients. Tafasitamab and rituximab target the B-cell surface proteins CD19 and CD20, respectively, and both antibodies feature overlapping modes of action , namely direct cytotoxicity, ADCC and ADCP. In this study, we show that the combination of tafasitamab and rituximab had additive and synergistic efficacy both in vitro and in vivo. Our findings shed new light on the underlying mechanism of the combination of both antibodies and lay the ground to translate the results into improved outcome for patients with aggressive lymphoma in future clinical trials.
2023-10-22 | GSE211829 | 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
Project description:The anti-leukemia activity of NK cells helps to prevent relapse during hematopoietic stem cell transplantation in leukemia patients. However, the factors that determine sensitivity or resistance of leukemia cells in the context of NK-mediated cytotoxicity are not well established. Here we performed a genome-wide CRIPSR screen in the human chronic-myelogenous-leukemia (CML) cell line K562 to identify genes that regulate vulnerability of leukemia cells to killing by primary human NK cells. Distribution of guide RNAs (gRNAs) in K562 cells that survived co-incubation with NK cells showed that loss of NCR3LG1, which encodes the ligand of the natural cytotoxicity receptor NKp30, protected K562 cells from killing. In contrast, loss of genes that regulate pathways for antigen-presentation and interferon-gamma-signaling increased the vulnerability of K562 cells. Addition of IFN-gamma neutralizing antibody increased the susceptibility of K562 cells to NK-mediated killing. Upregulation of MHC class I on K562 cells after co-incubation with NK cells was dependent on IFNGR2. Analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) showed that low IFNGR2 expression in cancer tissues associated with improved overall survival in acute myeloid leukemia (AML) and Kidney Renal Clear Cell Carcinoma (KIRC) patients. Our results showing that upregulation of MHC class I by NK-derived IFN-gamma leads to resistance to NK cytotoxicity suggest that targeting IFN-gamma responses might be a promising approach to enhance NK cell anti-cancer efficacy.
2019-10-24 | GSE139313 | GEO
Project description:Liver transplantation (LT) is a definitive treatment for end-stage liver disease and hepatocellular cancer. As donor-recipient HLA matching is not employed, there is potential for natural killer (NK) cell-mediated alloreactivity. Here we report that recipient NK cells exhibit a downregulated phenotype with reduced expression of activating receptors NKp30 and NKp46. We found associated hypofunctionality, with impaired NK cell cytotoxicity, degranulation and IFN-gamma production. Gene expression analysis using microarray and quantitative PCR identified significant downregulation of STAT-4 in LT with associated reduction in miR-155, a microRNA target of STAT-4 and a key regulator of NK differentiation. These data indicate that LT induces recipient NK cell tolerance through altered peripheral maturation at a step prior to the acquisition of inhibitory receptors for HLA class I.
2014-02-01 | E-MTAB-2132 | biostudies-arrayexpress
Project description:Natural Killer (NK) cells present natural cytotoxicity against tumor cells, although their activity is increased after activation. NK cell activation depends on a complex intracellular signaling process mediated by activating and inhibitory receptors and the functional outcome depends on the integration of the activating and inhibitory signals received. Soluble cytokines and/or ligands on target cells bind the NK cell receptors, and hence, influence the final NK cell response: attack versus ignorance. We used microarrays to detail the global programme of gene expression underlying NK cell activation by IL-2, a MHC-I-deficient target cell (K562)+IL-2 and an EBV-target cell (R69). PBLs from 4 different donors were activated by 100 U/ml IL-2; K562+IL-2 or R69 cells. After 5 days we obtained RNA and miRNA from naïve NK cells or from NK cells activated with the above mentioned stimuli, with more than 90% of purity. The 16 RNA samples were used to generate cDNA libraries that were hybridized on Human Gene 1.1ST arrays (Affymetrix) and analyzed with the Affymetrix Gene Chip Command Console Software v3.0 (AGCC 3.0, Affymetrix®) and the Expression Console Software v1.1 (Affymetrix®).
2014-09-09 | E-GEOD-50838 | biostudies-arrayexpress
Project description:NK cells are an essential component for the control of influenza infection, acting to both clear virus-infected cells and release antiviral cytokines. Engagement of the NK cell CD16-receptor by antibody-coated influenza-infected cells results in antibody-dependent cellular cytotoxicity (ADCC). Though NK cell-mediated ADCC is an important mechanism to control influenza, influenza infection itself may act to enhance the potency of NK cell ADCC. To understand if virus-infected cells increase NK cell activation, we co-cultured human PBMCs with influenza-infected human alveolar epithelial (A549) cells and evaluated the capacity of NK cells to mediate ADCC. Pre-incubation of PBMCs with influenza-infected target cells markedly enhanced the functionality of NK cells by ADCC antibodies in response to HA immune-complexes containing intravenous immunoglobulin (IVIG), allogenic target cells, with and without rituximab. Trans-well and supernatant transfer experiments showed that virus released into the supernatant is responsible for the enhanced functionality of NK cells, which is apparent at both the protein and RNA transcriptomic levels. Furthermore, cytokine multiplex data, RNA sequencing and cytokine blocking/supplementation experiments showed Type I interferons released from PBMCs were the primary mechanism of the influenza-induced increased NK cell functionality and ADCC potency. Importantly, the influenza infection-mediated increase in NK cell mediated anti-influenza ADCC was mimicked by the type I interferon agonist Poly-IC. This suggests a potential mechanism for enhancing monoclonal antibody therapies for influenza. We conclude that influenza-infection induced secretion of type I interferons enhances the ADCC capacity of NK cells and this pathway may potentially be manipulated to improve anti-influenza therapies.
2019-01-03 | GSE115203 | GEO
Project description:Natural Killer (NK) cells present natural cytotoxicity against tumor cells, although their activity is increased after activation.NK cell activation depends on a complex intracellular signaling process mediated by activating and inhibitory receptors and the functional outcome depends on the integration of the activating and inhibitory signals received. Soluble cytokines and/or ligands on target cells bind the NK cell receptors, and hence, influence the final NK cell response: attack versus ignorance. We used microarrays to detail the global programme of gene expression underlying NK cell activation by IL-2, a MHC-I-deficient target cell (K562)+IL-2 and an EBV-target cell (R69). PBLs from 4 different donors were activated by 100 U/ml IL-2; K562+IL-2 or R69 cells. After 5 days we obtained RNA and miRNA from naïve NK cells or from NK cells activated with the above mentioned stimuli, with more than 90% of purity. The 16 RNA samples were used to generate cDNA libraries that were hybridized on Human Gene 1.1ST arrays (Affymetrix) and analyzed with the Affymetrix Gene Chip Command Console Software v3.0 (AGCC 3.0, Affymetrix®) and the Expression Console Software v1.1 (Affymetrix®).
2014-09-09 | E-GEOD-50839 | biostudies-arrayexpress
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