Quantitative Analysis of Wild Type and CISH-/- induced pluripotent stem cell derived NK cells (iPSC-NK) Transcriptomes
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ABSTRACT:
PROVIDER: PRJNA631264 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11741581_1.fastq.gz | Fastqsanger.gz | |||
| SRR11741581_2.fastq.gz | Fastqsanger.gz | |||
| SRR11741582_1.fastq.gz | Fastqsanger.gz | |||
| SRR11741582_2.fastq.gz | Fastqsanger.gz | |||
| SRR11741583_1.fastq.gz | Fastqsanger.gz |
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Project description:We compared transcriptome of different types of NK cells including obtained from Umbilical Blood (UCB-NK) from 3 donors, both UCB56 NK cells that were isolated from the UCB unit as well as UCB34 NK cells that were differentiated from CD34+ cells, and derived from human iPSC (iPSC-NK), pre and post antigen presenting cell expansion. When comparing the similarity of the NK cells populations by the number of differentially expressed genes to iPSC NK cells, there were the pre and post expansion cells clustered together
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Project description:We compared transcriptome of different types of NK cells including obtained from peripheral Blood (PB-NK), derived from human ES cell, H9-NK, derived from human iPSC (iPSC-NK), derived from CD34+ cells from umbilical cord blood (UCB-NK), NKcell line (NK92) and 3 cancer cell lines (K562, Raji and Jurkat). When comparing the similarity of the NK cells populations by the number of differentially expressed genes to iPSC NK cells, there were the fewest differentially expressed genes in the comparison with the UCB NK cells, followed by the PB-NK cells, followed by the H9 embryonic stem cell derived-NK cells and lastly by the NK92 cell line.
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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.
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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.
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