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Pantothenate metabolism fuels T cell antitumor immunity

ABSTRACT: Pantothenate metabolism fuels T cell antitumor immunity

PROVIDER: PRJNA777572 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16762347_1.fastq.gz	Fastqsanger.gz
	SRR16762347_2.fastq.gz	Fastqsanger.gz
	SRR16762348_1.fastq.gz	Fastqsanger.gz
	SRR16762348_2.fastq.gz	Fastqsanger.gz
	SRR16762349_1.fastq.gz	Fastqsanger.gz

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Pantothenate metabolism fuels T cell antitumor immunity

Project description:Metabolic programming is a central regulator of T cell activation, differentiation and effector function. These metabolic processes are intricately linked to the anti-tumor properties of T cells and manipulation of T cell metabolism has shown promise in enhancing immunotherapy. To gain further insight into the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to interrogate the metabolic profile of three different CD8+ T cell subsets each with varying degrees of anti-tumor activity in murine models. These subsets include IFN-γ+ Tc1, IL-17+ Tc17 and IL-22+ Tc22 CD8+ effector subsets, of which Tc22 cells display the most robust anti-tumor activity. Here, we show that Tc22s were distinct in their up-regulation of the pantothenate/coenzyme A (CoA) pathway and requirement for oxidative phosphorylation (OXPHOS) for differentiation. Further investigation revealed that the exogenous administration of CoA metabolically reprogrammed T cells to increase OXPHOS and adopt the CD8+ Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). CoA-treated CD8+ T cells demonstrated enhanced anti-tumor function and persistence following adoptive transfer in murine tumor models. Treatment of mice with the CoA precursor pantothenate also enhanced the efficacy of anti-PD-L1 antibody therapy in preclinical models. These findings were extended to human melanoma patients, as we correlated increased pre-treatment plasma pantothenate levels with response to anti-PD1 antibody therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics and anti-tumor immunity.

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Project description:Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl levels. These elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.

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