Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1077715 | ENA |
REPOSITORIES: ENA
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Project description:Acute myeloid leukemia (AML) relapse is associated with a poor prognosis. Natural killer (NK) cells therapy induce leukemia remission; however, NK cells were susceptible to be exhausted post infusion. Determination of the mechanism of NK cell exhaustion in AML patients may provide insights for enhancing AML therapy. Here, we investigated NK cell exhaustion in relapsed AML patients post allo-HSCT based on phenotypic, functional, and RNA sequencing analyses. Compared with those from the complete remission and healthy control groups, NK cells from the relapsed group exhibited less maturity, higher inhibitory receptor expression and poorer cytotoxicity. AML cells could induce NK cell exhaustion through inhibition of PI3K-AKT pathway. Activation of PI3K-AKT was effective to increase NK cell cytotoxicity in exhausted NK cells. Excessive activation of the NKG2A/HLA-E axis is responsible for the inhibition of the PI3K-AKT pathway. Anti-HLA-E restored NK cell cytotoxicity against AML by increasing the phosphorylation of AKT in exhausted NK cells and knockout of the klrc1 in NK92 cells increased the phosphorylation of AKT and cytotoxicity against THP-1 cells. Moreover, blocking NKG2A was effective in controlling NK cell exhaustion and promoting cytotoxicity in AML mice. In summary, AML cells induced NK cell exhaustion via excessive activation of NKG2A/HLA-E axis and inhibition on PI3K-AKT pathway. Blocking the NKG2A axis is an effective way to reverse the inhibition of PI3K-AKT signaling on exhausted NK cells.
2025-01-31 | GSE252702 | GEO
Project description:Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.
2023-07-31 | GSE237922 | GEO
Project description:Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Notably, we identify a distinct CD161low CD218b+ NK cell subpopulation exhibiting the most pronounced proportional increase and transcriptomic changes upon venetoclax treatment.Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.
2023-07-31 | GSE237923 | GEO
Project description:CD226 plays a vital role in NK cell cytotoxicity, interacting with its ligands on tumor targets. Acute myeloid leukemia (AML) cells have developed mechanisms to escape NK cell cytotoxicity, including inducing downregulation of CD226 on NK cells. Induced pluripotent stem cell -derived NK (iPSC-NK) cells offer an important source of standardized off-the-shelf NK cell therapy to treat AML patients. In this study, we engineered iPSC-NK cells with CD226 to assess the ability of killing AML cells. iPSC-NK cells engineered with CD226 have a typical NK cell phenotype and demonstrate improved anti-AML activity and multiple cytokines releasing at low effector-to-target ratios. Transcriptomic analysis revealed upregulation of immune effector function pathways associated with cytotoxicity and immune activation in CD226-overexpression iPSC-NK cells. In an AML xenograft model, mice treated with CD226 overexpression iPSC-NK cells exhibited significantly reduced leukemia burden, prolonged survival, decreased systemic inflammation compared to those treated with Control iPSC-NK cells. Overall, our study provided evidence that iPSC derived-NK cells engineered with CD226 represent a promising candidate for off-the-shelf immunotherapy, particularly in AML and other CD226 ligand-expressing malignancies.
2025-03-23 | GSE292274 | GEO
Project description:Primary chimeric antigen receptor (CAR) natural killer (NK) cells show strong cytotoxic efficacy against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by tumor-mediated immune cell inactivation. Here, we report a novel strategy to overcome NK cell inhibition caused by the immune checkpoint NKG2A, which interacts with HLA-E expressed on AML blasts. We generated AML-specific CD33-directed CAR (CAR33)-KLRC1ko-NK cells with CRISPR/Cas9-based gene editing of the NKG2A-encoding KLRC1 gene. Single-cell multi-omic analyses revealed a higher proportion of activated cells in CAR33-NK- and CAR33-KLRC1ko-NK pools, which were preserved following AML-cell contact. This activated state of the CAR33-KLRC1ko-NK cells has been translated into improved antileukemic activity in vitro and in vivo against AML cell lines and primary blasts. This dual modification of primary NK cells has the potential to bypass the suppressive effect not only of AML but also in a broad range of other cancer identities.
2024-07-16 | GSE221552 | GEO
Project description:Natural killer (NK) cells are innate lymphocytes that play a critical role in host defense against viral infection. In addition to rapid effector cytokine production and direct cytotoxicity, NK cells exhibit features of adaptive immunity, including the capacity to undergo robust antigen-specific clonal proliferation and to generate immunological memory. However, the transcriptional programs and regulators governing dynamic NK cell responses to viral infection have not been fully uncovered. In this study, we identified Transcription factor 19 (TCF19) as a key driver of NK cell proliferation and calcium signaling in the context of mouse cytomegalovirus infection. Ablation of TCF19 was detrimental to NK cell clonal expansion and host protection against viral infection. Tcf19-/- NK cells were also unable to properly mobilize calcium downstream of antigen signaling to mediate cytotoxicity. Altogether, we find that TCF19 drives a transcriptional program that coordinates the innate and adaptive NK cell responses against viral infection.
2025-06-23 | GSE265814 | GEO
Project description:Urothelial carcinoma of the bladder, the second most prevalent cancer within the urothelial system, often evades immune recognition by natural killer (NK) cells, but studies have shown that cyproheptadine (CPH), an anti-histamine drug, exhibits anticancer effects in this carcinoma. Co-culturing CPH-treated cells with NKG2D-expressing NK92 cells resulted in enhanced NK-mediated lysis of UC cells, with RNA-seq analysis revealing increased expression of the NKG2D ligand ULBP2 in CPH-treated cells. We hypothesize that cyproheptadine as a epigenetic modifier enhances NK-mediated cytotoxicity by restoring NKG2D ligands and CCL3 and as a control we used entinostat a known FDA approved HDAC1/3 inhibitor. Targeting NK cells offers a promising strategy against urothelial carcinoma. Further analysis showed epigenetic regulation of ULBP2 expression with increased H3K27Ac active mark enrichment in CPH-treated cells. Overexpression of ULBP2 led to increased NK-mediated lysis, while knockdown reduced it in CPH-treated urothelial carcinoma cells. Additionally, CPH treatment enhanced the anti-tumor effect in a mouse model, likely due to increased NK and NKT cell infiltration. In summary, CPH triggers an innate immune response against urothelial carcinoma by promoting NK cell-mediated cytotoxicity through ULBP2 and CCL3 restoration.
2025-06-24 | GSE266660 | 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:T-cell recruiting bispecific antibodies (BsAbs) are in clinical development for relapsed/refractory acute myeloid leukemia (AML). Despite promising response rates, early clinical trials have failed to demonstrate durable responses. Here we investigated whether activation of the innate immune system through stimulator of interferon genes (STING) can enhance target-cell killing by a BsAb targeting CD33 (CD33 BiTE® molecule). Indeed, we show that cytotoxicity against AML mediated by the CD33 BiTE molecule AMG 330 can be greatly enhanced when combined with the STING agonist 2',3'-cyclic GMP–AMP (cGAMP). We used invitro cytotoxicity assays, immunoblotting, transcriptomic analyses, and extensive CRISPR–Cas9 knockout experiments to investigate the enhancing effect of cGAMP on the cytotoxicity of AMG330 against AML. Mechanistically, activated T cells prime target AML cells to STING activation through their effector cytokines interferon-gamma (IFNγ) and tumor necrosis factor (TNF), leading to increased production of typeI interferons and induction of interferon-stimulated genes. This feeds back to the T cells, leading to a further increase in effector cytokines and an overall cytotoxic T-cell phenotype, contributing to the beneficial effect of cGAMP in enhancing AMG330-mediated lysis. As such, we establish a key role for IFNγ in AMG 330-mediated cytotoxicity against AML cells, as well as in rendering AML cells responsive to STING agonism. Here, we propose to improve the efficacy of CD33-targeting BsAbs by combining them with a STING agonist.
2025-02-01 | GSE253398 | GEO
Project description:MicroRNAs (miRNAs) play important roles in regulating immune response of natural killer (NK) cells, a critical effectors against malignancy and infection. Here, miRNAs profiles of goat uterine NK (uNK) cells and peripheral blood NK (pNK) cells were examined, and a novel miRNAs, miR-1, that is lowly expressed in uNK cells compared to pNK cells were identified. We further demonstrated that miR-1 directly target TWEAK gene in NK cells, a negative regulator of NK cell cytotoxicity. Moreover, our data revealed that an increased miR-1 expression was observed in uNK cells incubated with somatic cell nuclear transfer (SCNT) conditioned medium compared to those incubated with in vitro fertilization (IVF) conditioned medium, and an inverse correlation was detected between miR-1 expression and TWEAK mRNA and protein expression in both groups. Interestingly, miR-1 mediated suppression of TWEAK in uNK cells in response to SCNT conditioned medium incubation was accompanied with an increased cytotoxicity and IFN-γ expression compared to control group. Furthermore, miR-1 inhibitor transfection abrogate the enhanced cytotoxicity of uNK cells incubated with SCNT conditioned medium, which was accompanied with an increased TWEAK expression. Taken together, our results demonstrated that TWEAK regulated by miR-1 may play a key role in regulating goat uNK cells cytotoxicity and IFN-γ expression levels. In particularly, miR-1 mediated suppression of TWEAK may involved in the increased cytotoxicity of uNK cells in response to SCNT embryo incubation. These results provide a resource for studying the roles of miRNAs in goat NK cell biology and contribute to a better understanding of the physiologic significance of miRNAs in the regulation of NK cell function.
2020-01-23 | GSE144088 | GEO