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

Abstract

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, <i>mtDNA^B6</i> and <i>mtDNA^NZB</i>, where <i>mtDNA^NZB</i> mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, <i>mtDNA^B6</i> Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas <i>mtDNA^NZB</i> Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the <i>mtDNA^NZB</i> mice exhibited strikingly impaired tumor growth while <i>mtDNA^B6</i> mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of <i>mtDNA^NZB</i> Teff cells increased mitochondrial gene expression while activation of <i>mtDNA^NZB</i> Treg cells impaired mitochondrial gene expression and resulted in <i>mtDNA^NZB</i> Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized <i>mtDNA^NZB</i> 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.