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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

GSE235311 Mus musculus Genome binding/occupancy profiling by high throughput sequencing 9 samples Submitted 2024/05/01 Platform GPL24247
Summary
Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of Complex I (CI) and II (CII), the gatekeepers for initiating electron flow, remains unclear. Here, we report that loss of CII, but not CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex I-antigen processing and presentation (MHC-APP) genes that is independent of interferon signaling. Furthermore, knock-out of MCJ, to promote electron entry preferentially via CI, provides proof-of-concept of ETC rewiring to achieve anti-tumor responses without side effects associated with an overall reduction in mitochondrial respiration in non-cancer cells. Our results hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
Published in
Manipulating mitochondrial electron flow enhances tumor immunogenicity
Mangalhara KC, Varanasi SK, Johnson MA et al. · Science (New York, N.Y.) 2023 · PMID 37733872 · doi:10.1126/science.abq1053
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Also filed as BioProject PRJNA985677 and SRA study SRP444933. Searching any of these in the dataset finder brings you back here.

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