|Title:||Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles||Authors:||Cheng A.N.
|Keywords:||inflammation; interferon inducers; tumor biomarkers; tumor escape; tumor microenvironment||Issue Date:||2020||Publisher:||BMJ Publishing Group||Journal Volume:||8||Journal Issue:||2||Start page/Pages:||e001372||Source:||Journal for ImmunoTherapy of Cancer||Abstract:||
Background Mitochondrial Lon is a chaperone and DNA-binding protein that functions in protein quality control and stress response pathways. The level of Lon regulates mitochondrial DNA (mtDNA) metabolism and the production of mitochondrial reactive oxygen species (ROS). However, there is little information in detail on how mitochondrial Lon regulates ROS-dependent cancer immunoescape through mtDNA metabolism in the tumor microenvironment (TME). Methods We explored the understanding of the intricate interplay between mitochondria and the innate immune response in the inflammatory TME. Results We found that oxidized mtDNA is released into the cytosol when Lon is overexpressed and then it induces interferon (IFN) signaling via cGAS-STING-TBK1, which upregulates PD-L1 and IDO-1 expression to inhibit T-cell activation. Unexpectedly, upregulation of Lon also induces the secretion of extracellular vehicles (EVs), which carry mtDNA and PD-L1. Lon-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME. Conclusions The levels of mtDNA and PD-L1 in EVs in patients with oral cancer function as a potential diagnostic biomarker for anti-PD-L1 immunotherapy. Our studies provide an insight into the immunosuppression on mitochondrial stress and suggest a therapeutic synergy between anti-inflammation therapy and immunotherapy in cancer. ?
|ISSN:||2051-1426||DOI:||10.1136/jitc-2020-001372||SDG/Keyword:||alpha interferon; CD3 antigen; CD4 antigen; CD8 antigen; endopeptidase La; gamma interferon; interferon; interferon regulatory factor 3; interleukin 2 receptor alpha; interleukin 6; Ku antigen; membrane protein; mitochondrial DNA; mitochondrial transcription factor A; programmed death 1 ligand 1; reactive oxygen metabolite; stimulator of interferon genes; toll like receptor 9; unclassified drug; CD274 protein, human; interferon; membrane protein; mitochondrial DNA; Pdcd1 protein, mouse; programmed death 1 ligand 1; programmed death 1 receptor; STING1 protein, human; Sting1 protein, mouse; tumor marker; 3B11 cell line; animal cell; animal experiment; animal model; Article; B16-F10 cell line; bone marrow derived macrophage; carcinogenesis; cell activation; DNA damage; DNA isolation; DOK cell line; enzyme linked immunosorbent assay; escape behavior; exosome; expression vector; female; flow cytometry; gene; gene overexpression; genetic transfection; HSC-3 cell line; human; human cell; immunoblotting; immunofluorescence assay; immunosuppressive treatment; innate immunity; luciferase assay; male; melanoma cell line; mitochondrial DNA disorder; mitochondrial DNA leakage; mouse; mouth squamous cell carcinoma; mRNA expression level; nonhuman; OECM-1 cell line; oxidative stress; RAW 264.7 cell line; real time polymerase chain reaction; signal transduction; spleen cell; TBK1 gene; transmission electron microscopy; tumor microenvironment; tumor volume; upregulation; animal; C57BL mouse; exosome; experimental melanoma; immunology; metabolism; signal transduction; Animals; B7-H1 Antigen; Biomarkers, Tumor; DNA, Mitochondrial; Extracellular Vesicles; Humans; Interferons; Male; Melanoma, Experimental; Membrane Proteins; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor; RAW 264.7 Cells; Signal Transduction; Transfection; Tumor Microenvironment
|Appears in Collections:||牙醫學系|
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