Hypoxia Induces Mitochondrial Defect That Promotes T Cell Exhaustion in Tumor Microenvironment Through MYC-Regulated Pathways
Hypoxia Induces Mitochondrial Defect That Promotes T Cell Exhaustion in Tumor Microenvironment Through MYC-Regulated Pathways
复制标题
缺氧诱导线粒体缺陷，通过 MYC 调节途径促进肿瘤微环境中 T 细胞耗竭
DOI：
10.3389/fimmu.2020.01906
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发表时间：
2020-08-21
影响因子：
7.3
通讯作者：
Li, Jiang
中科院分区：
文献类型：
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作者：
Liu, Yi-Na;Yang, Jie-Feng;Li, Jiang
T细胞耗竭是实体瘤免疫治疗的障碍。需要了解T细胞在实体瘤中形成这种表型的机制。在这里，缺氧，肿瘤微环境的一个特征，通过诱导线粒体缺陷导致T细胞耗竭（TExh）。在暴露于缺氧时，具有TExh表型的活化T细胞的特征在于线粒体片段化、ATP产生减少和线粒体氧化磷酸化活性降低。TExh表型与线粒体融合蛋白线粒体融合蛋白1（MFN 1）的下调和miR-24的上调相关。miR-24的过表达改变了许多代谢相关基因的转录，包括其靶基因MYC和成纤维细胞生长因子11（FGF 11）。MYC和FGF 11的下调诱导T细胞受体（TCR）刺激的T细胞中TExh分化、ATP产生减少和线粒体质量损失。此外，我们确定MYC调节FGF 11和MFN 1的转录。在鼻咽癌（NPC）组织中，T细胞表现出增加的耗竭频率和线粒体质量损失。此外，miR-24信号传导的抑制降低了裸鼠中NPC异种移植物的生长。我们的研究结果揭示了肿瘤环境中T细胞耗竭的机制，并为癌症免疫治疗提供了靶向线粒体代谢的潜在策略。
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 (TExh) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a TExh phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosphorylation activity. The TExh 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 MYC and fibroblast growth factor 11 (FGF11). Downregulation of MYC and FGF11 induces TExh 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 FGF11 and MFN1. 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.