Expression data from iPSC-derived mimetic Vγ9Vδ2 T cells and mimetic NK cells
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PROVIDER: PRJNA520837 | ENA |
REPOSITORIES: ENA
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Project description:We designed and demonstrated a synthetic strategy to derive mimetic Vγ9Vδ2 T cells endowed with NKRs from iPSCs. We used microarrays to compare mRNA expression profiles of such iPSC-derived mimetic Vγ9Vδ2 T cells with other peripheral blood lymphocytes.
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Project description:This dataset contains RNA-sequencing data from human induced pluripotent stem cell-derived natural killer (iPSC-NK) cells with or without SLC7A5 overexpression. The study was designed to investigate transcriptional changes associated with SLC7A5-mediated metabolic engineering in iPSC-NK cells, with a focus on cellular metabolism and antitumor function. These data were generated to characterize the molecular effects of SLC7A5 overexpression and to support the evaluation of metabolic remodeling in engineered iPSC-NK cells.
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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:Objectives: Vγ9Vδ2 T-cells are a subset of T-cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of both activatory and inhibitory receptors on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy. Methods: Expression of various activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry following activation and expansion using zoledronic acid (ZA) and Bacillus Calmette-Guérin (BCG). Expression of these markers and production of effector molecules was also examined following co-culture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also explored. Results: Vγ9Vδ2 T-cells expressed high levels of activatory markers both at baseline and following stimulation. Vγ9Vδ2 T-cells expressed variable levels of inhibitory checkpoint receptors with many being upregulated following stimulation. Expression of these markers is further modulated upon co- culture with tumour cells with changes reflecting activation and effector functions. Despite their high expression of inhibitory receptors when cultured with tumour cells expressing cognate ligands there was no effect on Vδ2+ T-cell cytotoxic capacity or cytokine production with immune checkpoint blockade. Conclusions: Our work suggests the expression of checkpoint receptors present on Vγ9Vδ2 T-cells which may provide a mechanism with the potential to be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. This work suggests important candidates for blockade by ICI therapy in order to increase the successful use of Vγ9Vδ2 T-cells in immunotherapy.
2023-01-02 | GSE221563 | GEO
Project description:Vγ9Vδ2 T cells play an important role in the development and progression of psoriasis vulgaris (PV), but how they promote skin inflammation and the molecular mechanisms underlying Vγ9Vδ2 T cell dysfunction are poorly understood. Here, we show that circulating Vγ9Vδ2 T cells are decreased and exhibit enhanced proliferation and increased production of IFN-γ and TNF-α in PV patients. Monocytes from PV patients express higher levels of the phosphoantigen sensor butyrophilin 3A1 (BTN3A1) than monocytes from healthy controls. Blockade of BTN3A1 suppresses Vγ9Vδ2 T cell activation and abolishes the difference in Vγ9Vδ2 T cell activation between PV patients and healthy controls. The CD14+ cells in PV skin lesions highly express BTN3A1 and juxtapose to Vδ2 T cells. In addition, IFN-γ induces the up-regulation of BTN3A1 on monocytes. Collectively, our results demonstrate a crucial role of BTN3A1 on monocytes in regulating Vγ9Vδ2 T cell activation and highlight BTN3A1 as a potential therapeutic target for psoriasis.
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Project description:Harnessing Features of Adaptive NK Cells to Generate iPSC-Derived NK Cells for Enhanced Immunotherapy
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Project description:To better understand the mechanisms underlying the different antitumor activity of Vγ9Vδ2-T cells induced by PA or OA, we performed the proteomic analysis of Vγ9Vδ2-T cells cultured under different conditions.
2025-07-14 | PXD064016 | Pride
Project description:Dozens of transplants generated from pluripotent stem cells are currently in clinical trials. The creation of patient-specific iPSCs makes personalized therapy possible due to their main advantage of immunotolerance. However, some reports have claimed recently that aberrant gene expression followed by proteome alterations and neoantigen formation can result in iPSCs recognition by autologous T-cells. Meanwhile, the possibility of NK-cell activation has not been previously considered. This study focused on the comparison of autologous and allogeneic immune response to iPSC-derived cells and isogeneic parental somatic cells used for reprogramming. Here we report that cells differentiated from iPSCs can be recognized by NK-cells rather than by autologous T-cells. We observed that iPS-fibro elicited a high level of NK-cell degranulation and cytotoxicity, while isogeneic parental skin fibroblasts used to obtain iPSCs barely triggered an NK-cell response. iPSC-derivatives with B2M knockout did not cause an additional increase in NK-cell activation, although they were devoid of HLA-I, the major inhibitory molecules for NK-cells. Transcriptome analysis revealed a significant imbalance of ligands for activating and inhibitory NK-cell receptors in iPS-fibro. Compared to parental fibroblasts, iPSC-derivatives had a reduced expression of HLA-I simultaneously with an increased gene expression of major activating ligands, such as MICA, NECTIN2, and PVR. The lack of inhibitory signals might be due to insufficient maturity of cells differentiated from iPSCs. In addition, we showed that pretreatment of iPS-fibro with proinflammatory cytokine IFNγ restored the ligand imbalance, thereby reducing the degranulation and cytotoxicity of NK-cells. In summary, we showed that iPSC-derived cells can be sensitive to the cytotoxic potential of autologous NK-cells regardless of HLA-I status. Thus, the balance of ligands for NK-cell receptors should be considered prior to iPSC-based cell therapies.
2023-03-01 | GSE212796 | GEO
Project description:Recent advancements in cancer immunotherapies have highlighted the potential of Vγ9Vδ2 T cells as key players in the immune response against cancer. These cells, initially recognized for their broad activity in combating infections and tumors, are now emerging as promising candidates for targeted immunotherapeutic strategies, including T cell Engagers (TCEs). However, like other immune cells, Vγ9Vδ2 T cells can enter a state of dysfunction and exhaustion within the tumor microenvironment, driven by factors such as TCR overstimulation, immunosuppressive cytokines (e.g., TGF-β), and hypoxia. While the mechanisms of T cell exhaustion have been extensively studied in in vivo CD8+ T cells, the lack of a murine Vγ9Vδ2 subset complicates the investigation and generation of large numbers of exhausted Vγ9Vδ2 T cells. To address this, we present a novel in vitro protocol for rapidly generating exhausted Vγ9Vδ2 T cells through co-culture with Zoledronate activated human tumor cells. We characterized the resulting cells using phenotypic, metabolomic, and transcriptomic analyses, comparing their profiles to published data on in vivo-exhausted cells. Furthermore, we measured the reactivation potential of these exhausted Vγ9Vδ2 T cells using anti-CD3 monoclonal antibodies, demonstrating that CD3 stimulation can partially reverse exhaustion and restore anti-tumor effector functions. Furthermore, exhausted Vγ9Vδ2 T cells retained some cytotoxic activity upon stimulation with T Cell Engagers, underscoring the versatility and applicability of our in vitro exhaustion model. This model offers a robust platform for the evaluation of novel immunotherapies targeting Vγ9Vδ2 T cells, facilitating preclinical assessments before transitioning to in vivo studies.
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