Dataset Information

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.

ABSTRACT: Although tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1? (PGC1?), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1? resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment.

SUBMITTER: Scharping NE

PROVIDER: S-EPMC5207350 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.

Scharping Nicole E NE Menk Ashley V AV Moreci Rebecca S RS Whetstone Ryan D RD Dadey Rebekah E RE Watkins Simon C SC Ferris Robert L RL Delgoffe Greg M GM

Immunity 20160802 2

Although tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced ...[more]

PMID: 27496732

Similar Datasets

Project description:Alzheimer's disease (AD) is an incurable neurodegenerative disease that is more prevalent in women. The increased risk of AD in women is not well understood. It is well established that there are sex differences in metabolism and that metabolic alterations are an early component of AD. We utilized a cross-species approach to evaluate conserved metabolic alterations in the serum and brain of human AD subjects, two AD mouse models, a human cell line, and two Caenorhabditis elegans AD strains. We found a mitochondrial complex I-specific impairment in cortical synaptic brain mitochondria in female, but not male, AD mice. In the hippocampus, Polβ haploinsufficiency caused synaptic complex I impairment in male and female mice, demonstrating the critical role of DNA repair in mitochondrial function. In non-synaptic, glial-enriched, mitochondria from the cortex and hippocampus, complex II-dependent respiration increased in female, but not male, AD mice. These results suggested a glial upregulation of fatty acid metabolism to compensate for neuronal glucose hypometabolism in AD. Using an unbiased metabolomics approach, we consistently observed evidence of systemic and brain metabolic remodeling with a shift from glucose to lipid metabolism in humans with AD, and in AD mice. We determined that this metabolic shift is necessary for cellular and organismal survival in C. elegans, and human cell culture AD models. We observed sex-specific, systemic, and brain metabolic alterations in humans with AD, and that these metabolite changes significantly correlate with amyloid and tau pathology. Among the most significant metabolite changes was the accumulation of glucose-6-phosphate in AD, an inhibitor of hexokinase and rate-limiting metabolite for the pentose phosphate pathway (PPP). Overall, we identified novel mechanisms of glycolysis inhibition, PPP, and tricarboxylic acid cycle impairment, and a neuroprotective augmentation of lipid metabolism in AD. These findings support a sex-targeted metabolism-modifying strategy to prevent and treat AD.

Dataset Information

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.

Publications

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets