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

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

PROVIDER: PRJNA814673 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18291916_1.fastq.gz	Fastqsanger.gz
	SRR18291916_2.fastq.gz	Fastqsanger.gz
	SRR18291917_1.fastq.gz	Fastqsanger.gz
	SRR18291917_2.fastq.gz	Fastqsanger.gz
	SRR18291918_1.fastq.gz	Fastqsanger.gz

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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: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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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

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