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Non-viral CISH locus-specific integrated IL-15-armored CAR-NK cells achieve potent anti-tumor efficacy via adaptive NK cell differentiation

ABSTRACT: Non-viral CISH locus-specific integrated IL-15-armored CAR-NK cells achieve potent anti-tumor efficacy via adaptive NK cell differentiation

PROVIDER: PRJNA1267492 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33692236_1.fastq.gz	Fastqsanger.gz
	SRR33692236_2.fastq.gz	Fastqsanger.gz
	SRR33692237_1.fastq.gz	Fastqsanger.gz
	SRR33692237_2.fastq.gz	Fastqsanger.gz
	SRR33692238_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Non-viral CISH locus-specific integrated IL-15-armored CAR-NK cells achieve potent anti-tumor efficacy via adaptive NK cell differentiation

Project description:Chimeric antigen receptor (CAR)-NK therapy has emerged as a highly promising alternative to CAR-T cell therapy, due to its remarkable efficacy and safety in hematological tumors. However, the efficacy of CAR-NK cells currently remains limited in solid tumors. Here, we successfully developed CISH locus-specific integrated CAR-NK cells using a non-viral mini-circular single-stranded DNA (mcssDNA)-based CRISPR/Cas9 targeted genome editing (mcssDNA/CRISPR/Cas9) technology via a single-step electroporation procedure. The developed CISH-knockout (CISH-KO) CAR-NK cells exhibited the enhanced proliferation and cytotoxicity against hepatocellular carcinoma (HCC) compared with conventional lentivirus-transduced CAR-NK (LV-CAR-NK) cells. Single-cell RNA sequencing analysis revealed an important subset of adaptive NK cells that were highly enriched in CISH-KO CAR-NK cells compared to LV-CAR-NK cells and showed the up-regulated JAK/STAT, energy metabolism and activating receptor signaling. Furthermore, non-viral CISH locus-specific integrated IL-15-armored CAR-NK cells were generated and achieved persistent tumor regression and a significant survival advantage in a lung metastatic mouse model of HCC. Collectively, our results demonstrate that non-viral CISH locus-specific integrated CAR-NK cells can be generated by a simplified, single-step manufacturing procedure and achieve potent efficacy against HCC, thus providing an innovative technology for CAR-NK cell therapy against solid tumors.

2025-05-26 | GSE298054 | GEO

Quantitative Analysis of Wild Type and CISH-/- induced pluripotent stem cell derived NK cells (iPSC-NK) Transcriptomes

Project description:We developed human CISH-knockout (CISH-/-) NK cells using an induced pluripotent stem cell-derived NK cell (iPSC-NK cell) platform. And compare transcriptomes of CISH-/- iPSC NK cells with wild type iPSC NK cells using RNA seq. RNA seq data suggested that genes involved in the JAK-STAT signaling pathway and lymphocyte activations were significantly activated in CISH-/- iPSC NK cells.

2020-05-09 | GSE150155 | GEO

CIS is a potent checkpoint in NK cell-mediated tumour immunity

Project description:Natural killer (NK) cells have evolved to detect and kill aberrant cells with this activity being governed by the cytokine interleukin (IL)-15 and foreign and self-ligands. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical negative regulator of IL-15 signalling in NK cells. Cish was rapidly induced in response to IL-15 and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by superior proliferation, survival, IFN-γ production and cytotoxicity towards tumours. This was associated with enhanced JAK/STAT signalling in Cish-deleted NK cells. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish-/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. This study has uncovered a potent checkpoint in NK cell-mediated tumour immunity and holds promise for novel immunotherapies directed at blocking CIS function.

2016-05-20 | GSE79409 | GEO

Cish inhibits CD8+ T cell immunity and disrupts proximal T cell receptor signaling

Project description:T cell receptor (TCR) signaling is a critical process in immunity to infectious disease and cancer. Recently, a genome-wide association study has implicated polymorphisms in the CISH locus with susceptibility to infectious diseases. However, the role of Cish in the immune responses and its molecular underpinnings remains unclear. Here we demonstrate that Cish deletion resulted in protection against viral infection and enhanced CD8+ T cell tumor immunity. Transcriptome profiling revealed a hyper-TCR activation signature in Cish-deficient CD8+ T cells. Subsequent analysis revealed an inhibitory role for Cish in PLCγ1 activation, ensuing Ca2+ release and downstream signaling. In the steady-state Cish was found to physically interact with PLCγ1, however, PLCγ1 was only found to be ubiquitinated after acute TCR stimulation in the presence of Cish. These data implicate Cish as a potent negative regulator of TCR signaling and T cell immunity to infection and cancer and may have significant clinical applications. 4 biological replicates from wild-type mice and 3 biological replicates from Cish knock-out (-/-) mice were analyzed.

2015-04-30 | E-GEOD-56328 | biostudies-arrayexpress

Cish inhibits CD8+ T cell immunity and disrupts proximal T cell receptor signaling

2015-04-30 | GSE56328 | GEO

Quantitative Analysis of Wild Type and CISH-/- induced pluripotent stem cell derived NK cells (iPSC-NK) Transcriptomes

Project description:Quantitative Analysis of Wild Type and CISH-/- induced pluripotent stem cell derived NK cells (iPSC-NK) Transcriptomes

| PRJNA631264 | ENA

Adaptive single-KIR+NKG2C+ NK cells expanded from superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia

Project description:Adoptive natural killer (NK) cell therapy in combination with hematopoietic stem cell transplantation (HSCT) can provide cure for acute myeloid leukemia (AML) but is in part dependent on variable NK cell reactivity. Adaptive NK cells are a highly potent NK cell subsets that can be utilized to maximize ‘missing-self’ reactivity against tumor cells. What this study adds: It describes a novel GMP-compliant protocol to expand clinically relevant numbers of adaptive NK cells from third-party ‘superdonors’. These NK cells provide strong reactivity in a mouse model of AML as well as against primary AML blasts ex vivo. How this study might affect research, practice or policy: These pre-clinical data demonstrate the feasibility of an NK cell-based cell therapy with a non-engineered and yet highly specific NK cell population, representing the first route to clinical testing of missing-self recognition.

2022-09-26 | GSE214042 | GEO

Adaptive single-KIR+NKG2C+ NK cells expanded from superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia

Project description:Describe a novel GMP-compliant protocol to expand clinically relevant numbers of adaptive NK cells from third-party ‘superdonors’. These NK cells provide strong reactivity in a mouse model of AML as well as against primary AML blasts ex vivo. How this study might affect research, practice or policy: These pre-clinical data demonstrate the feasibility of an NK cell-based cell therapy with a non-engineered and yet highly specific NK cell population, representing the first route to clinical testing of missing-self recognition.

2022-09-20 | E-MTAB-12228 | biostudies-arrayexpress

CMV infection drives adaptive epigenetic diversification of NK cells

Project description:The mechanisms underlying human NK cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins following cytomegalovirus (CMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Intriguingly, geneome-wide analyses revealed patterns of DNA methylation that were strikingly similar between CMV-associated adaptive NK cells and cytotoxic effector CD8+ T cells, but differed from those of canonical NK cells. A total of 23 samples were analyzed (4 sorted NK cell subsets and 2 sorted T cell subsets each from 4 individual donors). In one donor only 5 subsets were analyzed. Bisulfite-converted genomic DNA was hybridized to the Illumina Human Methylation450 BeadChip

2015-03-06 | E-GEOD-66562 | biostudies-arrayexpress

TGF-β and CIS inhibition overcomes NK cell suppression to restore anti-tumor immunity

Project description:Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8 T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK cell anti-tumor function is dependent on the cytokine interleukin (IL)-15. Ablation of the IL-15 signaling inhibitor CIS (Cish) enhances NK cell anti-tumor immunity by increasing NK cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK cell fitness via the production of immunosuppressive TGF-b, a suppression which occurs even in the presence of high IL-15 signaling. Here, we identified an unexpected interaction between CIS and the TGF-b signaling pathway in NK cells. Independently, Cish- and Tgfbr2- deficient NK cells are both hyper-responsive to IL-15 and hypo-responsive to TGF-b, with dramatically enhanced anti-tumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anti-cancer immunity.

2022-04-11 | GSE200134 | GEO

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