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TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through
Tianqi Lu1,2, Ziqi Zhang1, Zhenfei Bi1
1Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, China.
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.
Insights
Mitochondrial transcription factor A (TFAM) deficiency in dendritic cells (DCs) activates the STING pathway, reversing immune suppression and inhibiting tumor growth. This suggests TFAM knockout in DCs is a promising immunotherapy strategy.
Area of Science:
- Immunology
- Mitochondrial Biology
- Cancer Research
Background:
- Mitochondrial transcription factor A (TFAM) is crucial for mitochondrial DNA (mtDNA) stability and replication.
- Its role in immune cell regulation within tumors remains largely unexplored.
Purpose of the Study:
- To investigate the function of TFAM in immune regulation within the tumor microenvironment (TME).
- To explore the impact of TFAM deficiency in myeloid cells, specifically dendritic cells (DCs), on tumor progression.
Main Methods:
- Utilized mouse tumor models to assess TFAM deficiency effects on tumor progression and TME.
- Employed in vitro studies with bone marrow-derived dendritic cells (BMDCs) to analyze altered functions and pathways.
- Validated immune responses using ovalbumin (OVA) as a model antigen and STING inhibitors to confirm pathway activation.
Main Results:
- TFAM deletion in DCs caused mitochondrial dysfunction and mtDNA leakage, activating the cGAS-STING pathway.
- This activation enhanced antigen presentation by DCs.
- TFAM deficiency in DCs reversed immune-suppressive TME, inhibiting tumor growth and metastasis.
Conclusions:
- TFAM knockout in DCs ameliorates the immune-suppressive TME via STING pathway activation.
- Targeting TFAM in DCs presents a potential novel immunotherapy strategy for cancer treatment.
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