文章目录

线粒体DNA突变驱动有氧糖酵解以增强黑色素瘤的检查点阻断反应

原文发布日期：2024-01-29

英文摘要：

摘要翻译：

原文链接：

文章：

线粒体DNA突变驱动有氧糖酵解以增强黑色素瘤的检查点阻断反应

Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma

原文发布日期：2024-01-29

英文摘要：

The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.

摘要翻译：

细胞质基因组（mtDNA）编码了用于有氧呼吸磷酸化和代谢稳态的关键机器。肿瘤细胞质基因组是癌症基因组中最为 somatically突变的区域，但这些突变是否影响肿瘤生物学仍是待商榷的问题。我们通过引入多种小鼠模型，将 truncating 突变引入 mtDNA 所编码的第 I 亚基基因 Mt-Nd5。这些突变促进了 Warburg-like 的代谢转变，并在小鼠和人类中重塑了肿瘤微环境，从而一致地诱导了对肿瘤的反肿瘤免疫反应，其特征是]|[失去本生中性粒细胞。携带 mtDNA 突变的肿瘤对消agra受体阻断剂的耐受性依赖于中性粒细胞的存在，并且红氧失衡足以使 mtDNA 型癌细胞产生这种效果。患者切片中载有>50% mtDNA 异质突变的病灶对消agra受体阻断剂的反应率较 mtDNA 型癌提高了约 2.5 折，表明 mtDNA 突变是癌症代谢和肿瘤生物学的功能调节因子，具有潜在的治疗应用和治疗分层。