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Hypoxia Induces Mitochondrial Defect That Promotes T Cell Exhaustion in Tumor Microenvironment Through MYC-Regulated Pathways. | LitMetric

AI Article Synopsis

  • - T cell exhaustion is a significant challenge in treating solid tumors with immunotherapy, and understanding its mechanisms is crucial for developing effective treatments
  • - Hypoxia in the tumor microenvironment triggers mitochondrial dysfunction in T cells, leading to reduced energy production and altered metabolism, characterized by changes in specific proteins like mitofusin 1 and miR-24
  • - Research shows that targeting mitochondrial metabolism and signaling pathways related to miR-24 could help combat T cell exhaustion and improve cancer therapies, as demonstrated in studies with nasopharyngeal carcinoma models

Article Abstract

T cell exhaustion is an obstacle to immunotherapy for solid tumors. An understanding of the mechanism by which T cells develop this phenotype in solid tumors is needed. Here, hypoxia, a feature of the tumor microenvironment, causes T cell exhaustion (T) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a T phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosphorylation activity. The T phenotype is correlated with the downregulation of the mitochondrial fusion protein mitofusin 1 (MFN1) and upregulation of miR-24. Overexpression of miR-24 alters the transcription of many metabolism-related genes including its target genes and fibroblast growth factor 11 (). Downregulation of and induces T differentiation, reduced ATP production and a loss of the mitochondrial mass in T cell receptor (TCR)-stimulated T cells. In addition, we determined that MYC regulates the transcription of and . In nasopharyngeal carcinoma (NPC) tissues, the T cells exhibit an increased frequency of exhaustion and loss of mitochondrial mass. In addition, inhibition of miR-24 signaling decreases NPC xenograft growth in nude mice. Our findings reveal a mechanism for T cell exhaustion in the tumor environment and provide potential strategies that target mitochondrial metabolism for cancer immunotherapy.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472844PMC
http://dx.doi.org/10.3389/fimmu.2020.01906DOI Listing

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