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

Autor: Mahmood M; Cancer Research UK Scotland Institute, Glasgow, UK., Liu EM; Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Shergold AL; Cancer Research UK Scotland Institute, Glasgow, UK., Tolla E; Cancer Research UK Scotland Institute, Glasgow, UK., Tait-Mulder J; Cancer Research UK Scotland Institute, Glasgow, UK., Huerta-Uribe A; Cancer Research UK Scotland Institute, Glasgow, UK., Shokry E; Cancer Research UK Scotland Institute, Glasgow, UK., Young AL; Cancer Research UK Scotland Institute, Glasgow, UK., Lilla S; Cancer Research UK Scotland Institute, Glasgow, UK., Kim M; Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Park T; Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Boscenco S; Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Manchon JL; Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain., Rodríguez-Antona C; Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER, Madrid, Spain., Walters RC; Structural Biology Laboratory and York Biomedical Research Institute, Department of Chemistry, The University of York, York, UK., Springett RJ; Structural Biology Laboratory and York Biomedical Research Institute, Department of Chemistry, The University of York, York, UK., Blaza JN; Structural Biology Laboratory and York Biomedical Research Institute, Department of Chemistry, The University of York, York, UK., Mitchell L; Cancer Research UK Scotland Institute, Glasgow, UK., Blyth K; Cancer Research UK Scotland Institute, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Zanivan S; Cancer Research UK Scotland Institute, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Sumpton D; Cancer Research UK Scotland Institute, Glasgow, UK., Roberts EW; Cancer Research UK Scotland Institute, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Reznik E; Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. reznike@mskcc.org.; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. reznike@mskcc.org.; Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. reznike@mskcc.org., Gammage PA; Cancer Research UK Scotland Institute, Glasgow, UK. payam.gammage@glasgow.ac.uk.; School of Cancer Sciences, University of Glasgow, Glasgow, UK. payam.gammage@glasgow.ac.uk.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2024 Apr; Vol. 5 (4), pp. 659-672. Date of Electronic Publication: 2024 Jan 29.
DOI: 10.1038/s43018-023-00721-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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