FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308376187> ?p ?o ?g. }

• W4308376187 abstract "<h3>Background</h3> The signaling of key metabolic pathways in T cells within the tumor microenvironment (TME), strongly impacts their antitumor response. Cancer cells compete with T cells for essential nutrients such as glucose and amino acids; in addition, cancer cells produce T-cell inhibitory metabolites such as lactate and adenosine. Therefore, metabolic reprograming of T cells to confer adaptability to the TME is a promising therapeutic strategy for advanced cancers. <h3>Methods</h3> To identify detrimental metabolic genes for T-cell tumor infiltration, we performed an <i>in vivo</i> shRNA screen with a pooled metabolome library (~300 genes) in Pmel CD8 T cells adoptively transferred into B16 tumor-bearing mice. We identified genes whose disruption in T cells resulted in increased infiltration in B16 melanoma. <h3>Results</h3> We found that disruption of the PDHB gene enhances T-cell tumor infiltration. Pdhb encodes for the E1 Subunit Beta of the Pyruvate Dehydrogenase (PDHB), an enzyme linking glycolysis and the tricarboxylic acid cycle. We validated this result using CRISPR/Cas9 RNP transfection (>90% knockout efficacy) to knockout (KO) Pdhb in Pmel CD8 T cells. Our <i>in vivo</i> studies showed that PDHB KO improves T-cell infiltration and tumor rejection, vs non-targeting control T cells. PDHB KO cells produced higher IFNg levels and displayed improved tumoricidal capacity. The functional metabolomic analyses (seahorse assays) indicated that PDHB KO cells have an impaired mitochondrial function (reduced respiratory and FAO capacities) while having an increased glycolytic activity. The transcriptome and pathway analyses indicated that PDHB disruption, strongly induced lipid biosynthesis. Analyzing the most upregulated metabolites in the PDHB KO cells revealed that inosine, a product of adenosine metabolism, reported to serve as an alternative carbon source for T cells, was within the top 5 upregulated metabolites. The integrated transcriptome, metabolomics and pathway analyses indicated that PDHB KO cells display a metabolic reprograming with upregulation of unsaturated fatty acid biosynthesis, glycolysis/gluconeogenesis, pyruvate metabolism, chemokine signaling and purine metabolism. Remarkably, the transcriptome analysis suggests that the PDHB KO T cells have an expression pattern of Tscm/Tcm cells which might be associated with their capacity to survive within tumors. <h3>Conclusions</h3> In tumors characterized by glucose deprivation, the inosine upregulation by PDHB KO T cells might support T-cell function. Overall, our data suggests that PDHB disruption in T cells could contribute improving adoptive cell therapy. Thus, our study indicates that CRISPR-mediated metabolic reprograming of T cells could be a powerful approach for generating T cells able to overcome tumor-driven metabolic restrictions. <h3>Ethics Approval</h3> Animal protocol was approved by the University of South Florida, IACUC IS00008501." @default.
• W4308376187 created "2022-11-11" @default.
• W4308376187 creator A5027858037 @default.
• W4308376187 creator A5033798832 @default.
• W4308376187 creator A5059343454 @default.
• W4308376187 creator A5073029421 @default.
• W4308376187 creator A5082313246 @default.
• W4308376187 date "2022-11-01" @default.
• W4308376187 modified "2023-09-25" @default.
• W4308376187 title "189 CRISPR-mediated metabolic reprograming of adoptively transferred T cells to potentiate antitumor response" @default.
• W4308376187 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0189" @default.
• W4308376187 hasPublicationYear "2022" @default.
• W4308376187 type Work @default.
• W4308376187 citedByCount "0" @default.
• W4308376187 crossrefType "proceedings-article" @default.
• W4308376187 hasAuthorship W4308376187A5027858037 @default.
• W4308376187 hasAuthorship W4308376187A5033798832 @default.
• W4308376187 hasAuthorship W4308376187A5059343454 @default.
• W4308376187 hasAuthorship W4308376187A5073029421 @default.
• W4308376187 hasAuthorship W4308376187A5082313246 @default.
• W4308376187 hasBestOaLocation W43083761871 @default.
• W4308376187 hasConcept C121608353 @default.
• W4308376187 hasConcept C153911025 @default.
• W4308376187 hasConcept C154317977 @default.
• W4308376187 hasConcept C202751555 @default.
• W4308376187 hasConcept C502942594 @default.
• W4308376187 hasConcept C54355233 @default.
• W4308376187 hasConcept C55493867 @default.
• W4308376187 hasConcept C86803240 @default.
• W4308376187 hasConcept C95444343 @default.
• W4308376187 hasConcept C96232424 @default.
• W4308376187 hasConceptScore W4308376187C121608353 @default.
• W4308376187 hasConceptScore W4308376187C153911025 @default.
• W4308376187 hasConceptScore W4308376187C154317977 @default.
• W4308376187 hasConceptScore W4308376187C202751555 @default.
• W4308376187 hasConceptScore W4308376187C502942594 @default.
• W4308376187 hasConceptScore W4308376187C54355233 @default.
• W4308376187 hasConceptScore W4308376187C55493867 @default.
• W4308376187 hasConceptScore W4308376187C86803240 @default.
• W4308376187 hasConceptScore W4308376187C95444343 @default.
• W4308376187 hasConceptScore W4308376187C96232424 @default.
• W4308376187 hasLocation W43083761871 @default.
• W4308376187 hasOpenAccess W4308376187 @default.
• W4308376187 hasPrimaryLocation W43083761871 @default.
• W4308376187 hasRelatedWork W1965409546 @default.
• W4308376187 hasRelatedWork W1986240989 @default.
• W4308376187 hasRelatedWork W2046516922 @default.
• W4308376187 hasRelatedWork W2129882160 @default.
• W4308376187 hasRelatedWork W2413437467 @default.
• W4308376187 hasRelatedWork W2417756147 @default.
• W4308376187 hasRelatedWork W3207797839 @default.
• W4308376187 hasRelatedWork W4212820562 @default.
• W4308376187 hasRelatedWork W4307715326 @default.
• W4308376187 hasRelatedWork W2079932508 @default.
• W4308376187 isParatext "false" @default.
• W4308376187 isRetracted "false" @default.
• W4308376187 workType "article" @default.