Similar Datasets
Project description:An emerging cellular immunotherapy for cancer is based on the cytolytic activity of natural killer (NK) cells against a wide range of tumors. Although in vitro activation, or "priming," of NK cells by exposure to pro-inflammatory cytokines, such as interleukin (IL)-2, has been extensively studied, the biological consequences of NK cell activation in response to target cell interactions have not been thoroughly characterized. We investigated the consequences of co-incubation with K562, CTV-1, Daudi RPMI-8226, and MCF-7 tumor cell lines on the phenotype, cytokine expression profile, and transcriptome of human NK cells. We observe the downregulation of several activation receptors including CD16, CD62L, C-X-C chemokine receptor (CXCR)-4, natural killer group 2 member D (NKG2D), DNAX accessory molecule (DNAM)-1, and NKp46 following tumor-priming. Although this NK cell phenotype is typically associated with NK cell dysfunction in cancer, we reveal the upregulation of NK cell activation markers, such as CD69 and CD25; secretion of pro-inflammatory cytokines, including macrophage inflammatory proteins (MIP-1) α /β and IL-1β/6/8; and overexpression of numerous genes associated with enhanced NK cell cytotoxicity and immunomodulatory functions, such as FAS, TNFSF10, MAPK11, TNF, and IFNG. Thus, it appears that tumor-mediated ligation of receptors on NK cells may induce a primed state which may or may not lead to full triggering of the lytic or cytokine secreting machinery. Key signaling molecules exclusively affected by tumor-priming include MAP2K3, MARCKSL1, STAT5A, and TNFAIP3, which are specifically associated with NK cell cytotoxicity against tumor targets. Collectively, these findings help define the phenotypic and transcriptional signature of NK cells following their encounters with tumor cells, independent of cytokine stimulation, and provide insight into tumor-specific NK cell responses to inform the transition toward harnessing the therapeutic potential of NK cells in cancer.
| S-EPMC6594622 | biostudies-literature
Project description:An emerging cellular immunotherapy for cancer is based on the cytolytic activity of natural killer (NK) cells against a wide range of tumors. Although in vitro activation or ‘priming’ of NK cells by exposure to pro-inflammatory cytokines such as interleukin (IL)-2 has been extensively studied, the biological consequences of NK cell activation in response to target cell interactions are less characterized. Herein, we investigate the consequences of co-incubation with K562, CTV-1, Daudi and RPMI-8226 tumor cell lines on the phenotype, cytokine expression profile and transcriptome of human NK cells. We observe the downregulation of several activation receptors including CD16, CD62L, C-X-C chemokine receptor (CXCR)-4, natural killer group 2 member D (NKG2D), DNAX accessory molecule (DNAM)-1 and NKp46 following tumor-priming. Although this NK cell phenotype is typically associated with NK cell dysfunction in cancer, we show upregulation of NK cell activation markers such as CD69 and CD25, secretion of pro-inflammatory cytokines including macrophage inflammatory proteins (MIP-1) α /β and IL-1β/6/8 and overexpression of numerous genes associated with enhanced NK cell cytotoxicity and immunomodulatory functions such as FAS, TNFSF10, MAPK11, TNF and IFNG. Key signaling molecules exclusively affected by tumor-priming include MAP2K3, MARCKSL1, STAT5A, and TNFAIP3, which are specifically associated with NK cell cytotoxicity against tumor targets. Collectively, these findings help define the phenotypic and transcriptional signature of NK cells following their encounter with tumor cells, independent of cytokine stimulation, and provide insight into tumor-specific NK cell responses to inform the transition towards harnessing the therapeutic potential of NK cells in cancer.
2019-06-12 | GSE129800 | GEO
Project description:An emerging cellular immunotherapy for cancer is based on the cytolytic activity of natural killer (NK) cells against a wide range of tumors. Although in vitro activation or ‘priming’ of NK cells by exposure to pro-inflammatory cytokines such as interleukin (IL)-2 has been extensively studied, the biological consequences of NK cell activation in response to target cell interactions are less characterized. Herein, we investigate the consequences of co-incubation with K562, CTV-1, Daudi and RPMI-8226 tumor cell lines on the phenotype, cytokine expression profile and transcriptome of human NK cells. We observe the downregulation of several activation receptors including CD16, CD62L, C-X-C chemokine receptor (CXCR)-4, natural killer group 2 member D (NKG2D), DNAX accessory molecule (DNAM)-1 and NKp46 following tumor-priming. Although this NK cell phenotype is typically associated with NK cell dysfunction in cancer, we show upregulation of NK cell activation markers such as CD69 and CD25, secretion of pro-inflammatory cytokines including macrophage inflammatory proteins (MIP-1) α /β and IL-1β/6/8 and overexpression of numerous genes associated with enhanced NK cell cytotoxicity and immunomodulatory functions such as FAS, TNFSF10, MAPK11, TNF and IFNG. Key signaling molecules exclusively affected by tumor-priming include MAP2K3, MARCKSL1, STAT5A, and TNFAIP3, which are specifically associated with NK cell cytotoxicity against tumor targets. Collectively, these findings help define the phenotypic and transcriptional signature of NK cells following their encounter with tumor cells, independent of cytokine stimulation, and provide insight into tumor-specific NK cell responses to inform the transition towards harnessing the therapeutic potential of NK cells in cancer.
2019-06-12 | GSE130284 | GEO
Project description:Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures
| PRJNA534523 | ENA
Project description:Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures [Nanostring]
| PRJNA532851 | ENA
Project description:Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures [RNA-seq]
| PRJNA534526 | ENA
Project description:Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.
| S-EPMC5436500 | biostudies-literature
Project description:NK cells are phenotypically and functionally diverse lymphocytes due to variegated expression of a large array of receptors. NK-cell activity is tightly regulated through integration of receptor-derived inhibitory and activating signals. Thus, the receptor profile of each NK cell ultimately determines its ability to sense aberrant cells and subsequently mediate anti-viral or anti-tumor responses. However, an in-depth understanding of how different receptor repertoires enable distinct immune functions of NK cells is lacking. Therefore, we investigated the phenotypic diversity of primary human NK cells by performing extensive phenotypic characterization of 338 surface molecules using flow cytometry (n = 18). Our results showed that NK cells express at least 146 receptors on their surface. Of those, 136 (>90%) exhibited considerable inter-donor variability. Moreover, comparative analysis of CD56bright and CD56dim NK cells identified 70 molecules with differential expression between the two major NK-cell subsets and allowed discrimination of these subsets via unsupervised hierarchical clustering. These receptors were associated with a broad range of NK-cell functions and multiple molecules were not previously associated with predominant expression on either subset (e.g. CD82 and CD147). Altogether, our study contributes to an improved understanding of the phenotypic diversity of NK cells and its potential functional implications on a cellular and population level. While the identified distinct signatures in the receptor repertoires provide a molecular basis for the differential immune functions exerted by CD56bright and CD56dim NK cells, the observed inter-individual differences in the receptor repertoire of NK cells may contribute to a diverging ability to control certain diseases.
| S-EPMC7736243 | biostudies-literature
Project description:The mammalian immune response to infection is mediated by 2 broad arms, the innate and adaptive immune systems. Innate immune cells are a first-line defense against pathogens and are thought to respond consistently to infection, regardless of previous exposure, i.e., they do not exhibit memory of prior activation. By contrast, adaptive immune cells display immunologic memory that has 2 basic characteristics, antigen specificity and an amplified response upon subsequent exposure. Whereas adaptive immune cells have rearranged receptor genes to recognize the universe of antigens, natural killer (NK) cells are innate immune lymphocytes with a limited repertoire of germ-line encoded receptors for target recognition. NK cells also produce cytokines such as IFN-gamma (IFN-gamma) to protect the host during the innate response to infection. Herein, we show that cytokine-activated NK cells transferred into naïve hosts can be specifically detected 7-22 days later when they are phenotypically similar to naïve cells and are not constitutively producing IFN-gamma. However, they produce significantly more IFN-gamma when restimulated. This memory-like property is intrinsic to the NK cell. By contrast, memory-like NK cells do not express granzyme B protein and kill targets similarly to naïve NK cells. Thus, these experiments identify an ability of innate immune cells to retain an intrinsic memory of prior activation, a function until now attributed only to antigen-specific adaptive immune cells.
| S-EPMC2644138 | biostudies-literature
Project description:The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56bright state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56dim state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions.
| S-EPMC11291284 | biostudies-literature