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Comparison of gene expression by activated T-cells that express NKG2D-based CARs

ABSTRACT: Comparison of gene expression by activated T-cells that express NKG2D-based CARs

PROVIDER: PRJNA1049416 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27110368_1.fastq.gz	Fastqsanger.gz
	SRR27110368_2.fastq.gz	Fastqsanger.gz
	SRR27110369_1.fastq.gz	Fastqsanger.gz
	SRR27110369_2.fastq.gz	Fastqsanger.gz
	SRR27110370_1.fastq.gz	Fastqsanger.gz

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Comparison of gene expression by activated T-cells that express NKG2D-based CARs

Project description:NKG2D ligands are broadly expressed in cancer. To exploit this, we engineered an adaptor chimeric antigen receptor (CAR) termed NKG2D / Dap10-12 in which NKG2D is co-expressed with a fusion of Dap10 and the Dap12 endodomain. Dap10 was deployed to provide co-stimulation while Dap12 delivers an activation signal via a single immunoreceptor tyrosine-based activation motif (ITAM). NKG2D / Dap10-12 T-cells elicited compelling anti-tumor activity in several solid tumor xenograft models. Disease eradication was accompanied by sustained functional persistence, indicated by reproducible protection from secondary tumor re-challenge. Anti-cancer activity was consistently superior to an analog of a clinical stage linear CAR comprising an NKG2D-CD3 fusion. Mechanistically, functionality of NKG2D / Dap10-12 CAR T-cells was underpinned by transcriptomic re-programming to increase oxidative phosphorylation and ribosome biosynthesis..

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RNA-seq analysis of CAR-NKAE cells and CD45RA- CAR-T cells

Project description:CAR-T cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the anti-tumor activity of activated and expanded NK cells (NKAE) and CD45RA- T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and two of the treated mice remained disease-free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced anti-myeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR NK cell therapy for MM.

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RNAseq analysis of the effects of light and the carS mutation in Fusarium fujikuroi and Fusarium oxysporum

Project description:In the fungi Fusarium fujikuroi and Fusarium oxysporum, the induction of carotenogenesis by light and its deregulation in carS mutants, affected in a protein of the RING-finger family, are achieved on transcription of the structural genes of the pathway, some of them organized in a cluster. We have carried out global RNAseq transcriptomics analyses to investigate the relationship between the regulatory effects of light and the carS mutation. Either illumination or the absence of a functional carS gene exert wide effects on the transcriptome of F. fujikuroi, with a predominance of activated over repressed genes, and a greater functional diversity in the case of genes induced by light. The number of the latter decreases drastically in the carS mutant, indicating that the deregulation produced by the carS mutation affects the light response of many genes. In addition, light and CarS strongly influence the expression of some genes associated with stress responses. The effects of light and carS mutation on the F. oxysporum transcriptome were partially coincident with those in F. fujikuroi, indicating conservation of the objectives of their regulatory mechanisms. In conclusion, the CarS RING finger protein down-regulates many genes whose expression is up-regulated by light in the wild-type strains of the two Fusarium species investigated, indicating regulatory connections between the control by light and by the CarS protein.

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Ralstonia pseudosolanacearum CaRs-Mep

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The carP lncRNA is a carS-related regulatory element with broad effects on the Fusarium fujikuroi transcriptome

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Expression levels of genes of in vitro generated Th1 and Th17 cells from OT-II and OT-II x NKG2D-/- mice

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Project description:Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), that are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation. In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored how soluble NKG2DL affected NKG2D-CAR T cells´ cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells. In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by soluble NKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells. The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.

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