Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma Journal Article
| Authors: | Mahmood, M.; Liu, E. M.; Shergold, A. L.; Tolla, E.; Tait-Mulder, J.; Huerta-Uribe, A.; Shokry, E.; Young, A. L.; Lilla, S.; Kim, M.; Park, T.; Boscenco, S.; Manchon, J. L.; Rodríguez-Antona, C.; Walters, R. C.; Springett, R. J.; Blaza, J. N.; Mitchell, L.; Blyth, K.; Zanivan, S.; Sumpton, D.; Roberts, E. W.; Reznik, E.; Gammage, P. A. |
| Article Title: | Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma |
| Abstract: | 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). |
| Keywords: | genetics; mutation; mouse; animal; metabolism; animals; mice; melanoma; drug effect; cell line, tumor; immunology; neutrophil; tumor cell line; neutrophils; dna, mitochondrial; mitochondria; mitochondrion; glycolysis; oxidative phosphorylation; mitochondrial dna; tumor microenvironment; reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone); electron transport complex i; immune checkpoint inhibitor; humans; human; immune checkpoint inhibitors |
| Journal Title: | Nature Cancer |
| Volume: | 5 |
| Issue: | 4 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Publication status: | Published |
| Date Published: | 2024-04-01 |
| Online Publication Date: | 2024-01-29 |
| Start Page: | 659 |
| End Page: | 672 |
| Language: | English |
| DOI: | 10.1038/s43018-023-00721-w |
| PUBMED: | 38286828 |
| PROVIDER: | scopus |
| PMCID: | PMC11056318 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Ed Reznik -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work