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Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

ABSTRACT: Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

PROVIDER: PRJNA1224759 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32370034_1.fastq.gz	Fastqsanger.gz
	SRR32370034_2.fastq.gz	Fastqsanger.gz
	SRR32370035_1.fastq.gz	Fastqsanger.gz
	SRR32370035_2.fastq.gz	Fastqsanger.gz
	SRR32370036_1.fastq.gz	Fastqsanger.gz

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Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

Project description:Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

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Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

Project description:Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

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Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

Project description:Mitochondria regulate T cell functions and response to cancer immunotherapy. We show that pharmacologically induced PKM2 activation enhances mitochondria-dependent effector functions in mouse and human CD8 T cells and CAR-T cells. Multi-omics analysis and 13C-glucose tracer experiments showed that PKM2 activation alters one-carbon metabolism with decreased levels of methionine leading to hypomethylation of mitochondrial and nuclear DNA and enhanced expression of genes supporting mitochondrial biogenesis and respiratory complex formation in CD8 T cells. Functionally, PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells after adoptive cell therapy. Using preclinical melanoma and colon cancer models, we found that PKM2-agonist induced CD8 T cell-dependent anti-tumor responses that synergized with PD1 blockade therapy. Immunologically, PKM2 agonists resulted in enhanced activation and decreased exhaustion of effector T cells while reducing the numbers of suppressive FoxP3+ Treg cells in the tumor microenvironment. Anti-PD1 combination further enhanced the frequency and activation of tumor specific CD8 T cells in the tumors. Together, we show that PKM2 agonism modulates mitochondrial structure and function, leading to enhanced effector functions of cytotoxic lymphocytes. Hence, targeting PKM2 via pharmacologically available small molecules can be a clinically viable strategy for the enhancement of therapeutic potential of in-situ immune responses, adoptive cell therapy, and immune checkpoint blockade therapy

2025-05-01 | GSE289771 | GEO

Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

2025-05-01 | GSE289772 | GEO

Mitochondrial Pyruvate Carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria

Project description:The transporter which uptakes pyruvate into the mitochondria during pyruvate oxidation, called the Mitochondrial Pyruvate Carrier (MPC), was only recently identified. While the MPC has been studied in a variety of cell types, including cancer cells and stem cells, very little is known about the importance of MPC in immune cells. Here, we delete MPC from hematopoietic cells and measure its impact on T cell gene expression.

2020-04-27 | GSE122711 | GEO

Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-05-01 | GSE289773 | GEO

Mitochondrial Pyruvate Carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria

Project description:Mitochondrial Pyruvate Carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria

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miRNA expression between CD4+PD1+ and CD4+PD1- T cells

Project description:Recent success in cancer immunotherapy has come from the blockade of inhibitory receptors on T cells, such as programmed cell death-1, which can induce a state of T cell exhaustion upon constant antigen stimulation. Understanding miRNA regulation of PD1 can be useful to discover miRNAs for use in therapy or as prognostic markers in various diseases including cancer, autoimmunity and transplantation. We used microarrays to discover global miRNA expression changes upon PD1 upregulation and identified miRNAs that are both up- and down-regulated. B16F10 cells were injected subcutaneously into C57BL/6 mice and 16 days later CD4+PD1+ and CD4+PD1- were sorted from the lymph nodes and spleen for RNA extraction and hybridization on Affymetrix miRNA array.

2015-08-01 | E-GEOD-65208 | biostudies-arrayexpress

Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization

Project description:Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization

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PD1 completely suppresses the transcriptional response induced by the T cell receptor

Project description:Functional impairment of the immune response to chronic viral infections and malignancies is characterised by exhausted T cells, which do not respond to antigen. The cell surface receptor PD1 has been implicated in the maintenance of T cell exhaustion and is an attractive target for immunomodulatory approaches to the treatment of such conditions. However, the mechanisms by which PD1 signalling causes exhaustion and the exact response of T cells to PD1 activation are not clear although it has been suggested that PD1 up regulates a number of anti-proliferative factors. Here we perform cytokine and transcriptional profiling of uninfected primary human T cells to characterise these events. We find that PD1 completely prevents cytokine and transcrip- tional changes induced by CD3/28 stimulation. We do not see any factors specifically induced by PD1, including BATF or IL10 which have previously been linked to PD1 activity. Together with the work of others this confirms that PD1 is the sole effector of T cell exhaustion and that infection is responsible for BATF and IL10 up regulation. As a consequence future therapeutic strategies will be confined to the inhibition of PD1 and not a downstream effector.

2012-04-01 | E-MEXP-3410 | biostudies-arrayexpress

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