Manipulating mitochondrial electron flow enhances tumor immunogenicity

• 成果类型: Article
• 署名作者: Mangalhara, Kailash Chandra; Varanasi, Siva Karthik; Johnson, Melissa A.; Burns, Mannix J.; Rojas, Gladys R.; Esparza Molto, Pau B.; Sainz, Alva G.; Tadepalle, Nimesha; Abbott, Keene L.; Mendiratta, Gaurav; Chen, Dan; Farsakoglu, Yagmur; Kunchok, Tenzin; Hoffmann, Filipe Araujo; Parisi, Bianca; Rincon, Mercedes; Vander Heiden, Matthew G.; Bosenberg, Marcus; Hargreaves, Diana C.; Kaech, Susan M.; Shadel, Gerald S.
• 署名单位: Salk Institute; Yale University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Whitehead Institute; Children's Hospital Colorado; University of Colorado System; University of Colorado Anschutz Medical Campus; Yale University; Yale University; Yale University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9846
• DOI: 10.1126/science.abq1053
• 发表日期: 2023-09-22
• 页码: 1316-1323
• 关键词: chromosomes 1p; succinate; mutations; histone; losses; chain; 3q

摘要

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 through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects 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.