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CREM is a regulatory checkpoint of CAR and IL-15 signaling in NK cells

ABSTRACT: CREM is a regulatory checkpoint of CAR and IL-15 signaling in NK cells

PROVIDER: PRJNA1111772 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29031500.fastq.gz	Fastqsanger.gz
	SRR29031501.fastq.gz	Fastqsanger.gz
	SRR29031438_1.fastq.gz	Fastqsanger.gz
	SRR29031438_2.fastq.gz	Fastqsanger.gz
	SRR29031439_1.fastq.gz	Fastqsanger.gz

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CREM is a regulatory checkpoint of CAR and IL-15 signaling in NK cells

Project description:This is a preclinical study investigating the role of CREM transcription factor in CAR NK cells. We found thata CREM is a regulatory checkpoint induced by CAR CD3z signaling and IL-15 stimulation that leads to suppression of NK cell function. CREM KO enhances the anti-tumor efficacy of CAR NK cells.

2025-03-14 | GSE267523 | GEO

Transcriptome Sequencing of Neo-2/15 stimulated CAR-NK cells

Project description:We performed transcriptome sequencing on Neo-2/15 stimulated CAR NK cells,to shed light on the function and phenotype changes of CAR-NK cells stimulated by IL-2 and Neo-2/15.

2023-12-31 | GSE243530 | GEO

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

NK cells engineered with a IL-15/IL-15Rα complex and CD19-targeted CAR show in vitro expansion and tumor regression in a murine xenograft model of B-cell leukemia in vivo

Project description:Natural killer (NK) cells are an attractive therapeutic approach as alternative chimeric antigen receptor (CAR) carriers and unlike T cells, offer their use in allogeneic settings. The translation of NK cells into the clinic is still hampered by the inability of CAR-NK cells to expand in vitro and in vivo. Adoptive transfer of CAR-NK cells holds the promise of therapeutic benefit with a lower rate of adverse events due to the absence of GvHD and cytokine release syndrome. However, adoptive transfer of CAR-NK cells has not yet achieved breakthrough clinical results, and further improvement of CAR-NK cells is necessary. Here, we demonstrated that a fourth-generation CD19-targeted CAR (CAR.19) co-expressing IL-15 linked to its receptor IL-15/IL-15Rα (CAR.19-IL-15/IL-15Rα) significantly enhanced NK-92 cell proliferation, proinflammatory cytokine secretion, and cytotoxic activity against B-cell cancer cell lines in vitro and in a xenograft mouse model. Surprisingly, CAR construct comprising the IL-15/IL-15Rα was superior to CAR co-expressing the soluble form of IL-15 in terms of sustained proliferation, viability, but importantly also in their ability to control CD19+ B-cell lymphoma in a murine xenograft model. Together with the results of the systematic analysis of the transcriptome of activated NK-92 CAR variants, this supports the notion that IL-15/IL-15Rα comprising fourth-generation CARs may overcome the limitations of NK cell-based targeted tumor therapies in vivo by providing the necessary growth and activation signals

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Project description:Human induced pluripotent stem cells (iPSCs) offer a promising source for producing standardized, off-the-shelf CAR-NK products. However, the complex and time-consuming iPSC-NK (iNK) manufacturing challenges clinical use. Here, we identified LiPSC-GR1.1 as a superior iPSC line for iNK production. By engineering LiPSC-GR1.1 with a mesothelin (MSLN)-targeting CAR and IL-15, we achieved efficient robust differentiation of iPSCs into mature and activated iNKs, which demonstrated enhanced tumor-killing efficacy, superior tumor-homing, and vigorous proliferation. Single-cell transcriptomic analysis revealed that TGF-β-producing tumor cells upregulated MHC molecules and downregulated MSLN expression post-CAR-IL-15 iNK treatment. Tumor-infiltrating CAR-IL-15 iNKs exhibited high levels of CAR, IL-15, and NK-activating receptors, negligible checkpoint exhaustion markers, and extremely low levels of NK suppressive factors CISH, TGFBR2, and BATF, enabling them to sustain activation, metabolic fitness, and effective tumor killing within the TGF-β-rich hypoxic tumor microenvironment. Overall, we developed a MSLN.CAR-IL-15-engineered GR1.1-iNK product with enhanced anti-tumor efficacy for solid tumor treatment.

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Project description:Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has demonstrated safety and feasibility in clinic; yet, limited efficacy resulted from intrinsic dysfunction and extrinsic depression remains to be addressed. T cells provide a multifaceted complementation to NK cell-mediated response. Here, we designed a novel CD19-targeted CAR-NK armored with secreted interleukin (IL) -15 and CCL21 (15x21 CAR-NK) that are capable of recruiting and cooperating with T cells. These 15x21 CAR-NK cells possess excellent capacities for cytotoxicity, cytokine production, and effector molecule expression in vitro. The cooperation with T cells presents benefits of alleviating mutual exhaustion and boosting the expression of effector molecules/receptors, thus promoting the elimination of tumor cells efficiently. In addition, 15x21 CAR-NK cells were also highly enriched PI3K/AKT/mTOR pathway, associating with downstream pro-survival signaling, anti-apoptosis ability, and mitochondrial fitness. Collectively, our study highlights the intrinsic superiority and extrinsic T-cell cooperative advantages of 15x21 CAR-NK cells, providing a promising strategy for NK-cell based immunotherapy.

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Project description:The purpose of this experiment was two-fold. The first was to examine how the gene expression profile changes over time in C7R-CAR NK cells. C7R is a constitutively active IL-7 receptor that provides persistent activation of STAT5. The second was to examine the differential gene expression in C7R CAR NK cells or CAR NK treated with exogenous IL-15 (exIL15) after 2 weeks of stimulation.

2024-09-30 | GSE277499 | GEO

RNA squencing of human NK cells activated with IL-15 or IL-12, IL-15, and IL-18

Project description:NK cells are an emerging cancer cellular therapy and potent mediators of anti-tumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces remissions in acute myeloid leukemia (AML) patients. However, the dynamic molecular changes that occur after memory-like differentiation in vitro are unclear. Here, control or ML NK cells purified from normal donor PBMC were generated in vitro. Briefly, RosetteSep-purified NK cells were incubated in IL-12, IL-15, and IL-18, or low-dose IL-15 as a control for 16-18 hours. Control or cytokine-activated NK cells were washed three times and cultured for 6 days in low-dose IL-15, which is required for NK cell survival. After 6 days, RNA was isolated from control and memory-like (ML) NK cells (IL12/15/18 activation) and RNA-sequencing performed. Because the transcription factor GATA-3 was increased specifically in ML NK cells, we hypothesized ML NK cells would exhibit a GATA-3 gene signature compared to control NK cells. Indeed, using GSEA, a significant gene signature was associated with ML NK cell differentiation. These data support the role for GATA-3 in regulating the ML NK cell molecular program.

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Transcriptome Sequencing of Neo-2/15 stimulated CAR-NK cells

Project description:Transcriptome Sequencing of Neo-2/15 stimulated CAR-NK cells

| PRJNA1018869 | ENA