Children’s Hospital of Philadelphia Researchers Identify Important Role of Mitochondria in Immune Response to Cancer

Researchers from Children’s Hospital of Philadelphia (CHOP) discovered a connection between mitochondrial DNA and tumor progression. The preclinical findings may help guide clinical understanding of tumor development and provide evidence of a novel way of suppressing tumor progression. The findings were recently published in the journal Proceedings of the National Academy of Sciences.

The mitochondria, or “batteries” of our cells, have their own DNA known as mitochondrial DNA (mtDNA), which is completely distinct from the DNA found in the nucleus of our cells. Like DNA, mtDNA can have its own variations associated with diseases, and prior research suggests that mtDNA variation is associated with altered cancer severity. However, the underlying pathways responsible for increased cancer risk are largely unknown.

To better analyze the connection between certain mtDNA lineages and cancer, researchers in the Center for Mitochondrial and Epigenomic Medicine (CMEM) at CHOP developed an animal model with two naturally occurring mtDNA lineages: mtDNAB6 and mtDNANZB. mtDNANZB is known to have altered mitochondrial oxidative phosphorylation (OXPHOS) which in turn generates more mitochondrial reactive oxygen species (mROS). mROS have been associated with mtDNA damage and disruption of the regular mitochondrial cycle of producing energy for the body.

“Our research revealed that normal mtDNA variants can influence T cell function, providing new mechanistic insights into how mtDNA variants affect disease risk by regulating immune cell activity and paving the way for novel therapeutic approaches targeting mitochondria,” said first study author Tal Yadeni, PhD, a principal investigator at the Metabolic Center at Sheba Medical Center who began this research during a postdoctoral fellowship at CHOP.

Using a transplantation model, researchers found that the mtDNANZB lineage model had a more reactive immune response. When the models were tested with melanoma or colon cancer cells, mtDNANZB lineage model exhibited impaired tumor growth, whereas the mtDNAB6 allowed rapid tumor growth. Further investigation revealed that the mtDNANZB model exhibited reduced immunosuppressive function in regulatory T (Treg) cells while demonstrating enhanced functionality in T effector cells.

To explore potential treatment options involving mitochondria, the researchers found that mCAT, an antioxidant enzyme that specifically targets the mitochondria, normalized T regulatory cell function in both transplant and tumor roles of the mtDNANZB lineage model. These findings suggest that increased mROS promotes dysfunction of T regulatory cells. Additionally, the researchers found that anti-PD-L1 therapy, an immune checkpoint inhibitor that kills tumor cells and is used to treat certain cancers, did not modulate these effects, which suggests that mtDNA variants and proper mitochondrial functional management provide an independent approach for treating certain cancers.

“Our study demonstrated that variations in mitochondrial DNA can modulate both the adaptive immune system as well as the innate immune system through immune cell metabolism,” said senior study author Douglas C. Wallace, PhD, director of the CMEM at CHOP. “These findings suggest that modulating immune cell mitochondrial function may provide a unique approach for cancer immunotherapy.”

This study was supported by National Institutes of Health grants R01CA259635 and R01AG078814. The Rosa26-LSL-mCAT mouse model was developed with the support of the Chao Family Comprehensive Cancer Center Transgenic Mouse Facility Shared Resource, and National Cancer Institute grant P30CA062203.

Yardeni et al, “Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling.” Proc Natl Acad Sci U S A. Online January 3, 2025. DOI: 10.1073/pnas.2417252121.