Manipulating mitochondrial electron flow enhances tumor immunogenicity.
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| Title: | Manipulating mitochondrial electron flow enhances tumor immunogenicity. |
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| Authors: | Mangalhara, Kailash Chandra, Varanasi, Siva Karthik, Johnson, Melissa A., Burns, Mannix J., Rojas, Gladys R., Esparza Moltó, Pau B., Sainz, Alva G., Tadepalle, Nimesha, Abbott, Keene L., Mendiratta, Gaurav, Dan Chen, Farsakoglu, Yagmur, Tenzin Kunchok, Hoffmann, Filipe Araujo, Parisi, Bianca, Rincon, Mercedes, Vander Heiden, Matthew G., Bosenberg, Marcus, Hargreaves, Diana C., Kaech, Susan M. |
| Source: | Science (pre-March 2025). 9/22/2023, Vol. 381 Issue 6664, p1316-1323. 8p. 5 Diagrams. |
| Subjects: | Immune response, Electron transport, Mitochondria, Electrons, Tumor growth, T cell receptors, Amyloid beta-protein precursor, Photosystems |
| Abstract: | Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of 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–antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially throughCI, provides proof of conceptof ETCrewiringtoachieve antitumor responses withoutsideeffects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of 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–antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially throughCI, provides proof of conceptof ETCrewiringtoachieve antitumor responses withoutsideeffects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.abq1053 |
