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TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway
BACKGROUND: Mitochondrial transcription factor A (TFAM) is a transcription factor that maintains mitochondrial DNA (mtDNA) stabilization and initiates mtDNA replication. However, little is known about the immune regulation function and TFAM expression in immune cells in the tumors. METHODS: Mouse tu...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980377/ https://www.ncbi.nlm.nih.gov/pubmed/36858460 http://dx.doi.org/10.1136/jitc-2022-005430 |
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author | Lu, Tianqi Zhang, Ziqi Bi, Zhenfei Lan, Tianxia Zeng, Hao Liu, Yu Mo, Fei Yang, Jingyun Chen, Siyuan He, Xuemei Hong, Weiqi Zhang, Zhe Pi, Ruyu Ren, Wenyan Tian, Xiaohe Wei, Yuquan Luo, Min Wei, Xiawei |
author_facet | Lu, Tianqi Zhang, Ziqi Bi, Zhenfei Lan, Tianxia Zeng, Hao Liu, Yu Mo, Fei Yang, Jingyun Chen, Siyuan He, Xuemei Hong, Weiqi Zhang, Zhe Pi, Ruyu Ren, Wenyan Tian, Xiaohe Wei, Yuquan Luo, Min Wei, Xiawei |
author_sort | Lu, Tianqi |
collection | PubMed |
description | BACKGROUND: Mitochondrial transcription factor A (TFAM) is a transcription factor that maintains mitochondrial DNA (mtDNA) stabilization and initiates mtDNA replication. However, little is known about the immune regulation function and TFAM expression in immune cells in the tumors. METHODS: Mouse tumor models were applied to analyze the effect of TFAM deficiency in myeloid cell lineage on tumor progression and tumor microenvironment (TME) modification. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were used in the investigation of the altered function and the activated pathway. OVA was used as the model antigen to validate the activation of immune responses in vivo. STING inhibitors were used to confirm the STING activation provoked by Tfam deficient in DCs. RESULTS: The deletion of TFAM in DCs led to mitochondrial dysfunction and mtDNA cytosolic leakage resulting in the cGAS-STING pathway activation in DCs, which contributed to the enhanced antigen presentation. The deletion of TFAM in DCs has interestingly reversed the immune suppressive TME and inhibited tumor growth and metastasis in tumor models. CONCLUSIONS: We have revealed that TFAM knockout in DCs ameliorated immune-suppressive microenvironment in tumors through STING pathway. Our work suggests that specific TFAM knockout in DCs might be a compelling strategy for designing novel immunotherapy methods in the future. |
format | Online Article Text |
id | pubmed-9980377 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-99803772023-03-03 TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway Lu, Tianqi Zhang, Ziqi Bi, Zhenfei Lan, Tianxia Zeng, Hao Liu, Yu Mo, Fei Yang, Jingyun Chen, Siyuan He, Xuemei Hong, Weiqi Zhang, Zhe Pi, Ruyu Ren, Wenyan Tian, Xiaohe Wei, Yuquan Luo, Min Wei, Xiawei J Immunother Cancer Basic Tumor Immunology BACKGROUND: Mitochondrial transcription factor A (TFAM) is a transcription factor that maintains mitochondrial DNA (mtDNA) stabilization and initiates mtDNA replication. However, little is known about the immune regulation function and TFAM expression in immune cells in the tumors. METHODS: Mouse tumor models were applied to analyze the effect of TFAM deficiency in myeloid cell lineage on tumor progression and tumor microenvironment (TME) modification. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were used in the investigation of the altered function and the activated pathway. OVA was used as the model antigen to validate the activation of immune responses in vivo. STING inhibitors were used to confirm the STING activation provoked by Tfam deficient in DCs. RESULTS: The deletion of TFAM in DCs led to mitochondrial dysfunction and mtDNA cytosolic leakage resulting in the cGAS-STING pathway activation in DCs, which contributed to the enhanced antigen presentation. The deletion of TFAM in DCs has interestingly reversed the immune suppressive TME and inhibited tumor growth and metastasis in tumor models. CONCLUSIONS: We have revealed that TFAM knockout in DCs ameliorated immune-suppressive microenvironment in tumors through STING pathway. Our work suggests that specific TFAM knockout in DCs might be a compelling strategy for designing novel immunotherapy methods in the future. BMJ Publishing Group 2023-03-01 /pmc/articles/PMC9980377/ /pubmed/36858460 http://dx.doi.org/10.1136/jitc-2022-005430 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Lu, Tianqi Zhang, Ziqi Bi, Zhenfei Lan, Tianxia Zeng, Hao Liu, Yu Mo, Fei Yang, Jingyun Chen, Siyuan He, Xuemei Hong, Weiqi Zhang, Zhe Pi, Ruyu Ren, Wenyan Tian, Xiaohe Wei, Yuquan Luo, Min Wei, Xiawei TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway |
title | TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway |
title_full | TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway |
title_fullStr | TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway |
title_full_unstemmed | TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway |
title_short | TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway |
title_sort | tfam deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cgas-sting pathway |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980377/ https://www.ncbi.nlm.nih.gov/pubmed/36858460 http://dx.doi.org/10.1136/jitc-2022-005430 |
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