Similar Datasets
Project description:Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.
| S-EPMC10923096 | biostudies-literature
Project description:Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
| S-EPMC10168291 | biostudies-literature
Project description:Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ HA-CAR-T cells commonly express CD39 and CD73, which mediate proximal steps in Ado generation. Here we sought to enhance HA-CAR-T cell potency by knocking out CD39, CD73 or adenosine receptor 2a (A2aR), but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced HA-CAR-T functionality. Similarly, and to a greater extent, exposure of HA-CAR-T cells to INO augmented HA-CAR-T cell function and induced hallmark features of T cell stemness. INO induced profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency HA-CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
2023-12-18 | GSE250439 | GEO
Project description:Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ HA-CAR-T cells commonly express CD39 and CD73, which mediate proximal steps in Ado generation. Here we sought to enhance HA-CAR-T cell potency by knocking out CD39, CD73 or adenosine receptor 2a (A2aR), but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced HA-CAR-T functionality. Similarly, and to a greater extent, exposure of HA-CAR-T cells to INO augmented HA-CAR-T cell function and induced hallmark features of T cell stemness. INO induced profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency HA-CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
2023-12-18 | GSE250442 | GEO
Project description:The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.
| S-EPMC11456602 | biostudies-literature
Project description:The intensive nutrient requirements needed to sustain T cell activation and proliferation combined with competition for nutrients within the tumor microenvironment raise the prospect that glucose availability may limit CAR T cell function. Here, we sought to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observed that GLUT1OE in CAR-T cells increased glucose consumption, glycolysis, glycolytic reserve and oxidative phosphorylation and these effects were associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induced broad metabolic reprogramming associated with increased glutathione41 mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secreted more proinflammatory cytokines and mediated enhanced cytotoxicity in vitro and demonstrated superior tumor control and persistence in vivo. Our collective findings support a model wherein glucose availability is rate limiting for optimal effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE provides a new approach to augment antitumor immune function.
2024-08-19 | GSE275152 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-12-31 | E-GEOD-73602 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-06-09 | GSE234307 | GEO
Project description:Chemokines critically orchestrate the tumorigenesis, metastasis, and stemness features of cancer cells that lead to poor outcomes. High plasma levels of transforming growth factor-β1 (TGFβ1) correlate with poor prognostic features in advanced lung cancer patients, thus suggesting the importance of TGFβ1 in the lung tumor microenvironment. However, the role of chemokines in TGFβ1-induced tumor stemness features remains unclear. Here, we clarify the previously undocumented role of CXCL1 in TGFβ1-induced lung cancer stemness features. CXCL1 and its receptor CXCR2 were significantly upregulated in TGFβ1-induced lung cancer stem cells (CSCs). CXCL1 silencing (shCXCL1) suppressed stemness gene expression, tumorsphere formation, colony formation, drug resistance, and in vivo tumorigenicity in TGFβ1-induced lung tumorspheres. Immunohistochemistry staining showed that patients with stage II/III lung cancer had higher expression levels of CXCL1. The levels of CXCL1 were positively associated with lymph node metastasis and correlated with the expression of the CSC transcription factor Oct-4. Furthermore, online database analysis revealed that CXCL1 expression was negatively correlated with lung cancer survival in patients. Patients with high TGFβ1/CXCL1/CD44 co-expression had a worse survival rate. We suggest that CXCL1 serves as a crucial factor in TGFβ1-induced stemness features of lung cancer.
| S-EPMC10903253 | biostudies-literature
Project description:CD19-targeting chimeric antigen receptors (CARs) with CD28 and CD3ζ signaling domains have been approved by the US FDA for treating B cell malignancies. Mutation of immunoreceptor tyrosine-based activation motifs (ITAMs) in CD3ζ generated a single-ITAM containing 1XX CAR, which displayed superior antitumor activity in a leukemia mouse model. Here, we investigated whether the 1XX design could enhance therapeutic potency against solid tumors. We constructed both CD19- and AXL-specific 1XX CARs and compared their in vitro and in vivo functions with their wild-type (WT) counterparts. 1XX CARs showed better antitumor efficacy in both pancreatic and melanoma mouse models. Detailed analysis revealed that 1XX CAR-T cells persisted longer in vivo and had a higher percentage of central memory cells. With fluorescence resonance energy transfer (FRET)-based biosensors, we found that decreased ITAM numbers in 1XX resulted in similar 70-kDa zeta chain-associated protein (ZAP70) activation, while 1XX induced higher Ca2+ elevation and faster extracellular signal-regulated kinase (Erk) activation than WT CAR. Thus, our results confirmed the superiority of 1XX against two targets in different solid tumor models and shed light on the underlying molecular mechanism of CAR signaling, paving the way for the clinical applications of 1XX CARs against solid tumors.
| S-EPMC9840118 | biostudies-literature