CAR T cells targeting uPAR are effective senolytics
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA607785 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11123962.fastq.gz | Fastqsanger.gz | |||
| SRR11123963.fastq.gz | Fastqsanger.gz | |||
| SRR11123964.fastq.gz | Fastqsanger.gz | |||
| SRR11123965.fastq.gz | Fastqsanger.gz | |||
| SRR11123966.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:Cellular senescence is a stress-response program characterized by stable cell cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a potent tumor suppressive mechanism that prevents the expansion of premalignant cells and plays a beneficial role in certain wound healing responses. Pathologically, the aberrant accumulation of senescent cells in response to chronic tissue damage produces an inflammatory milieu that contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis. Accordingly, experimental approaches to eliminate senescent cells from damaged tissues in mice can ameliorate symptoms of these pathologies and even promote longevity. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells targeting senescent cells can serve as effective senolytics. We identify the urokinase plasminogen activator receptor (uPAR) as a cell surface protein that is broadly induced during senescence and demonstrate that uPAR-specific CAR T cells efficiently target senescent cells in vitro and in vivo. Administration of uPAR-targeting CAR T cells improves the survival of mice harboring lung adenocarcinoma cells treated with a senescence inducing drug combination, and eliminates fibrosis in mice treated with carbon tetrachloride or on a non-alcoholic steatohepatitis (NASH)-inducing diet. These results establish the potential of senolytic CAR T therapy for a range of senescence-associated diseases.
2020-04-18 | GSE145642 | GEO
Project description:Senescent cells accumulate in organisms over time as a result of tissue damage and impaired immune surveillance and are thought to contribute to age-related tissue decline1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness3-7. While small-molecule drugs capable of eliminating senescent cells (known as ‘senolytics’) partially replicate these phenotypes, many have uncertain mechanisms of action and all require continuous administration to be effective. As an alternative approach, we previously developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis8. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells in aged animals. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, the beneficial effects of senolytic CAR T cells are long lasting; single administration of a low dose is sufficient to achieve long-term therapeutic and preventive effects.
2023-12-08 | GSE243616 | GEO
Project description:Identification of lipid senolytics targeting senescent cells through ferroptosis induction
| PRJNA1166889 | ENA
Project description:Chimeric antigen receptor (CAR)-engineered T cell therapy holds promise for targeting myeloid malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, autologous approaches pose significant challenges in manufacturing and patient selection, emphasizing the need for off-the-shelf cell products. In this study, we systematically characterized primary AML and MDS patient samples, identifying a unique therapeutic opportunity for CAR-engineered invariant natural killer T (CAR-NKT) cell therapy. Utilizing a clinically guided culture method, we generated allogeneic IL-15-enhanced CD33-targeting CAR-NKT (Allo15CAR33-NKT) cells through HSPC engineering and an ex vivo, feeder-free HSPC differentiation culture. These cells demonstrated potent antitumor efficacy against blast cells via multiple tumor-targeting mechanisms. In vivo, Allo15CAR33-NKT cells exhibited effective tumor homing, expansion, and persistence, characterized by high effector function and low exhaustion propensity. Furthermore, these cells synergized with hypomethylating agent (HMA) treatment, which upregulated CD1d and NK ligand expression on tumor cells, enhancing susceptibility to Allo15CAR33-NKT cell-mediated killing. Notably, Allo15CAR33-NKT cells displayed minimal off-tumor effects against hematopoietic precursors, and low risks of graft-versus-host disease and cytokine release syndrome, highlighting their substantial therapeutic potential for myeloid malignancies.
2025-01-01 | GSE270430 | GEO
Project description:Chimeric antigen receptor T cells (CAR-T) therapy has not yet been fully explored in solid tumors. Human epidermal growth factor receptor-2(HER2) is widely expressed in cancers. Investigators have developed anti-HER2 CAR-modified T cells and validated the efficiency targeting HER2-positive cancer in preclinical studies. This study is aimed to confirm its adverse effects including cytokine storm response and any other adverse effects. In addition, CAR-T cells persistence, tumor elimination and disease status after treatment will be evaluated.
| 2210681 | ecrin-mdr-crc
Project description:Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging their regenerative capacity is reduced, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein in other tissues and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, and mucosal immune function in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms.
2025-10-13 | GSE233431 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging their regenerative capacity is reduced, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein in other tissues and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, and mucosal immune function in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms.
2025-10-13 | GSE301534 | GEO
Project description:Through phenotypic drug screening, we identified a novel class of lipid senolytics that selectively eliminated a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice. Extensive mechanistic studies reveal that these lipids induce ferroptotic cell death by exploiting the iron-rich and ROS-prone characteristics of senescent cells, offering a new therapeutic strategy to target senescence in aging and age-related diseases.
2024-10-07 | GSE278372 | GEO
Project description:The discovery of effective senolytics offers a promising approach for treating many age-related diseases. In this study, we employed a phenotypic drug discovery approach, combining drug screening and drug design, to identify and develop novel senolytic agents based on the flavonoid fisetin. We successfully developed two novel flavonoid analogs, SR29384 and SR31133, which demonstrated significantly enhanced senolytic activities compared to fisetin. These analogs showed broad-spectrum efficacy in eliminating various senescent cell types, reducing tissue senescence, extending healthspan in mice, and prolonging lifespan in Drosophila. Through RNA sequencing, machine learning, and computational screening, our mechanistic studies suggest that these novel flavonoid senolytics may target PARP1, BCL2L1, and CDK2 to induce senescent cell death.
2024-10-27 | GSE279349 | GEO
Project description:Allogeneic HSPC-engineered CD33-targeting CAR-NKT cells synergize with hypomethylating agents for effective and safe treatment of myeloid malignancies
| PRJNA1126626 | ENA