Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
Menée à l'aide de lignées cellulaires et de modèles murins de mélanome, cette étude démontre que des mutations somatiques au niveau du gène Mt-Nd5 de l'ADN mitochondrial peuvent induire la glycolyse aérobique et sensibiliser les cellules cancéreuses aux inhibiteurs de point de contrôle immunitaire
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.
Nature Cancer , article en libre accès, 2024