Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling

• 成果类型: Article
• 署名作者: Yardeni, Tal; Olali, Arnold Z.; Chen, Hsiao-Wen; Wang, Liqing; Halton, Jeffrey A.; Zenab, Angi; Morrow, Ryan; Butic, Arrienne; Murdock, Deborah G.; Waymire, Katrina G.; Macgregor, Grant R.; Boursi, Ben; Beier, Ulf H.; Hancock, Wayne W.; Wallace, Douglas C.
• 署名单位: University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Chaim Sheba Medical Center; Tel Aviv University; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Pennsylvania; University of California System; University of California Irvine; Tel Aviv University; Chaim Sheba Medical Center; Tel Aviv University; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9025
• DOI: 10.1073/pnas.2417252121
• 发表日期: 2025-01-07
• 关键词: rna-seq; promotes; metabolism; mtdna; heteroplasmy; inhibition; mutations; tumorigenicity; expression; increase

摘要

Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA- cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNAB6 and mtDNANZB, where mtDNANZB mitochondria generate more oxidative phosphorylation (OXPHOS)- derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNAB6Foxp3+ T regulatory (Treg) cells supported long- term allograft survival, whereas mtDNANZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNANZB mice exhibited strikingly impaired tumor growth while mtDNAB6 mice showed Treg- dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNANZB Teff cells increased mitochondrial gene expression while activation of mtDNANZB Treg cells impaired mitochondrial gene expression and resulted in mtDNANZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNANZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti- PD- L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.