Laboratory 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.
The Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China.
J Immunother Cancer. 2023 Mar;11(3). doi: 10.1136/jitc-2022-005430.
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.
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 deficient in DCs.
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.
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.
线粒体转录因子 A（TFAM）是一种转录因子，可维持线粒体 DNA（mtDNA）的稳定性并启动 mtDNA 复制。然而，对于肿瘤中免疫细胞的免疫调节功能和 TFAM 表达知之甚少。
应用小鼠肿瘤模型分析骨髓细胞系中 TFAM 缺失对肿瘤进展和肿瘤微环境（TME）修饰的影响。在体外，使用原代小鼠骨髓来源的树突状细胞（BMDC）研究改变的功能和激活途径。OVA 被用作模型抗原来验证体内免疫反应的激活。使用 STING 抑制剂来确认 DC 中缺失引起的 DC 中 cGAS-STING 途径的激活。
DC 中 TFAM 的缺失导致线粒体功能障碍和 mtDNA 胞质渗漏，导致 DC 中 cGAS-STING 途径的激活，这有助于增强抗原呈递。有趣的是，DC 中 TFAM 的缺失逆转了免疫抑制性 TME 并抑制了肿瘤模型中的肿瘤生长和转移。
我们揭示了 DC 中 TFAM 的缺失通过 STING 途径改善了肿瘤中的免疫抑制微环境。我们的工作表明，DC 中特定的 TFAM 缺失可能是未来设计新型免疫疗法的一种有吸引力的策略。
