Dataset Information

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

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 (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.

SUBMITTER: Liu YN

PROVIDER: S-EPMC7472844 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Liu Yi-Na YN Yang Jie-Feng JF Huang Dai-Jia DJ Ni Huan-He HH Zhang Chuan-Xia CX Zhang Lin L He Jia J Gu Jia-Mei JM Chen Hong-Xia HX Mai Hai-Qiang HQ Chen Qiu-Yan QY Zhang Xiao-Shi XS Gao Song S Li Jiang J

Frontiers in immunology 20200821

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<sub>Exh</sub>) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a T<sub>Exh</sub> phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosp ...[more]

PMID: 32973789

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Project description:Recent studies demonstrate that sustained hypoxia induces the robust accumulation of leukocytes and mesenchymal progenitor cells in pulmonary arteries (PAs). Since the factors orchestrating hypoxia-induced vascular inflammation are not well-defined, the goal of this study was to identify mediators potentially responsible for recruitment to and retention and differentiation of circulating cells within the hypoxic PA. We analyzed mRNA expression of 44 different chemokine/chemokine receptor, cytokine, adhesion, and growth and differentiation genes in PAs obtained via laser capture microdissection in adjacent lung parenchyma and in systemic arteries by RT-PCR at several time points of hypoxic exposure (1, 7, and 28 days) in Wistar-Kyoto rats. Analysis of inflammatory cell accumulation and protein expression of selected genes was concomitantly assessed by immunochemistry. We found that hypoxia induced progressive accumulation of monocytes and dendritic cells in the vessel wall with few T cells and no B cells or neutrophils. Upregulation of stromal cell-derived factor-1 (SDF-1), VEGF, growth-related oncogene protein-alpha (GRO-alpha), C5, ICAM-1, osteopontin (OPN), and transforming growth factor-beta (TGF-beta) preceded mononuclear cell influx. With time, a more complex pattern of gene expression developed with persistent upregulation of adhesion molecules (ICAM-1, VCAM-1, and OPN) and monocyte/fibrocyte growth and differentiation factors (TGF-beta, endothelin-1, and 5-lipoxygenase). On return to normoxia, expression of many genes (including SDF-1, monocyte chemoattractant protein-1, C5, ICAM-1, and TGF-beta) rapidly returned to control levels, changes that preceded the disappearance of monocytes and reversal of vascular remodeling. In conclusion, sustained hypoxia leads to the development of a complex, PA-specific, proinflammatory microenvironment capable of promoting recruitment, retention, and differentiation of circulating monocytic cell populations that contribute to vascular remodeling.

Project description:BackgroundDiabetes mellitus and pancreatic cancer are intimately related. Our previous studies showed that high levels of blood glucose promote epithelial-mesenchymal transition of pancreatic cancer. In this study, we evaluated the relationship between hyperglycemia and hypoxic tumor microenvironments.MethodsHIF-1? expression was evaluated by immunohistochemistry in clinical pancreatic cancer tissues with or without diabetes mellitus. Statistcal analysis was performed to explore the relationship between HIF-1? expression and pathological features of patients with pancreatic cancer. In vivo and in vitro models was established to detect whether a hyperglycemia environment could cause hypoxia in the pancreatic parenchyma and promote pancreatic cancer. In addition, we also tested the effect of HIF-1? siRNA on the high glucose-induced invasive and migratory abilities of BxPC-3 cells in culture.ResultOur data showed that pancreatic cancer patients with diabetes had a higher level of HIF-1? expression as well as biliary duct invasion and larger tumor volumes than individuals in the euglycemic group. Diabetic nude mice treated with streptozotocin (STZ) exhibited larger tumors and were more likely to develop liver metastasis than control mice. Acinar cells of the pancreas in diabetic mice showed an obvious expansion of the endoplasmic reticulum and increased nuclear gaps as well as chromatin close to the cellular membrane in some acinar cells. The expression area for Hypoxyprobe-1 and HIF-1? in the diabetic orthotopic xenograft group was larger than that in the control group. The expression level of HIF-1? in the BxPC-3 cancer cell line increased in response to high glucose and CoCl2 concentrations. The high glucose-induced invasive ability, migratory capacity and MMP-9 expression were counter-balanced by siRNA specific to HIF-1?.ConclusionOur results demonstrate that the association between hyperglycemia and poor prognosis can be attributed to microenvironment hypoxia in pancreatic cancer.

Dataset Information

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

Publications

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

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