| Autor: |
Markowitz GJ; Weill Cornell Medicine., Ban Y; Weill Cornell Medicine., Tavarez DA; Weill Cornell Medicine., Yoffe L; Weill Cornell Medicine., Podaza E; Weill Cornell Medicine., He Y; Weill Cornell Medicine., Martin MT; Weill Cornell Medicine., Crowley MJP; Weill Cornell Medicine., Sandoval TA; Weill Cornell Medicine., Gao D; Weill Cornell Medicine., Martin ML; Weill Cornell Medicine., Elemento O; Weill Cornell Medicine., Cubillos-Ruiz JR; Weill Cornell Medicine., McGraw TE; Weill Cornell Medicine., Altorki NK; Weill Cornell Medicine., Mittal V; Weill Cornell Medicine. |
| Jazyk: |
angličtina |
| Zdroj: |
Research square [Res Sq] 2023 Sep 21. Date of Electronic Publication: 2023 Sep 21. |
| DOI: |
10.21203/rs.3.rs-3356477/v1 |
| Abstrakt: |
TCF1 high progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, however the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 high central memory-like phenotype and increased responsiveness to PD-1 blockade in vivo . PKM2 KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites, and increased PPP cycling as determined by 1,2 13 C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells towards a TCF1 high population, generated a unique transcriptional landscape, enhanced tumor control in mice in combination with PD-1 blockade, and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state amenable to checkpoint blockade. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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