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This study provided the first evidence that upon PD-1 ligation, activated T cells had increased expression of CPT1a, fatty acid oxidation and are unable to engage in glycolysis. This study suggested that the enhancement of FAO may provide a mechanism for the longevity of T cells receiving PD-1 signals in patients with cancer.
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This study demonstrated that mitochondrial ultrastructure controls T cell fate and metabolism. They showed that memory T cells have fused mitochondria and favored oxidative phosphorylation and FAO in memory T cells. In contrast, mitochondrial fission in effector cells leads to cristae expansion and promoted aerobic glycolysis. This is the first study suggesting that enforcing fusion can improve T cell based adoptive immunotherapy against tumors.
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Together with Ref. [44], this paper describes the Warburg metabolism enables tumor cells to restrict glucose availability to T cells, suppressing anti-tumor immunity. Chang CH et al., demonstrated that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. HO PC et al. shows that phosphoenolpyruvate carboxykinase 1 (PCK1) overexpression in T cells increased effector function that results in restricted tumor growth.
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Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche
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1117–1131.e14 This study demonstrated that inhibition of PHD Proteins in CD4+ T cells results in increased HIF1 activity, elevated aerobic glycolysis and heightened effector differentiation. Furthermore, this study highlighted that pharmacological inhibition of PHD proteins in CD4+ T cells can improve T cell effector function and adoptive cell transfer immunotherapy against B16 melanoma.
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