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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

ABSTRACT: Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

PROVIDER: PRJNA985677 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24974078.fastq.gz	Fastqsanger.gz
	SRR24974079.fastq.gz	Fastqsanger.gz
	SRR24974080.fastq.gz	Fastqsanger.gz
	SRR24974081.fastq.gz	Fastqsanger.gz
	SRR24974082.fastq.gz	Fastqsanger.gz

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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity

Project description:Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity

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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

Project description: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.

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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [bulk RNA-seq]

Project description:Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [bulk RNA-seq]

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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [scRNA-seq and scTCR-seq]

Project description:Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [scRNA-seq and scTCR-seq]

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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [bulk RNA-seq]

Project description:Loss of antigen presentation by MHCI is a common mechanism of tumor immune evasion. Mitochondrial oxidative phosphorylation (OXPHOS) capacity influences MHCI expression, but the underlying molecular mechanisms remain unclear. Here, we demonstrate that the relative flow of electrons through complex I or II of the mitochondrial electron transport chain (ETC) regulates MHCI expression and antigen presentation in cancer cells. Specifically, reducing electron flow from complex II increases mitochondrial succinate which activates transcription of MHCI and antigen processing and presentation (APP) genes. These phenotypes are independent of the interferon (IFN) signaling pathway and driven by succinate-mediated enzymatic inhibition of lysine-specific demethylases, KDM5A/B and destabilization of polycomb repressor complex 2 (PRC2). Finally, knockout of the mitochondrial Complex I inhibitor protein, MCJ, preferentially reduces electron flow through Complex II and increases succinate which drives an enhanced antigen-dependent CD8+ T cell response to mouse melanoma tumors in vivo. These findings suggest that the mitochondrial ETC can be manipulated therapeutically to enhance antitumor immune responses independently of IFNγ.

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Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Project description:Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

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Project description:Cancer cells reprogram their metabolism to support cell growth and proliferation in harsh environments. To assess how human cells respond to defective mitochondrial respiration, we analyzed metabolomics profiles in cells with deficient electron transport chain (ETC). We found that ETC deficiency induces an accumulation of purine nucleotides. Additionally, we revealed that ETC blockade suppressed de novo purine nucleotide biosynthesis while enhanced purine salvage. This metabolic rewiring of purine nucleotide biosynthesis is not regulated at the transcriptional level. Instead, stable isotope tracing experiments showed that ETC blockade promoted the oxidative branch of pentose phosphate pathway to elevate phosphoribosyl diphosphate to drive purine salvage. In summary, our findings delineate how cells remodel purine metabolism in response to ETC blockade, and uncover a new metabolic vulnerability in tumors with low respiration.

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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-31 | GSE198348 | GEO

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

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