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A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma
Stefano Pierini1, Chongyun Fang2, Stavros Rafail2
1Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy; and.
Abstract:
Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell-based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer.
Insights
Tumor-associated mitochondrial antigens (TAMAs) can trigger antitumor immune responses. Researchers developed a dendritic cell vaccine using mitochondrial proteins, demonstrating its effectiveness in fighting cancer and providing durable protection.
Area of Science:
- Mitochondrial biology
- Cancer immunology
- Immunotherapy
Background:
- Mitochondria generate cellular energy through oxidative phosphorylation.
- Mitochondrial DNA (mtDNA) mutations occur in various cancers due to reactive oxygen species.
- Altered mitochondrial proteins (tumor-associated mitochondrial antigens or TAMAs) are potentially immunogenic.
Purpose of the Study:
- To investigate the immunogenicity of TAMAs.
- To develop and evaluate a dendritic cell-based vaccine using mitochondrial proteins for cancer immunotherapy.
Main Methods:
- Enriched mitochondrial proteins from RENCA tumor cells were used to pulse dendritic cells.
- Generated a cellular tumor vaccine.
- Sequenced mtDNA from RENCA cells to identify mutations.
- Developed peptide vaccines from mutated mitochondrial-encoded molecules (COX1 and ND5).
Main Results:
- The dendritic cell-based RENCA mitochondrial lysate vaccine induced a cytotoxic T cell response in vivo.
- The vaccine provided durable protection against RENCA cell challenge in both prophylactic and therapeutic settings.
- Mutations in COX1 and ND5 were identified in RENCA cell mtDNA.
- Peptide vaccines from COX1, but not ND5, showed therapeutic efficacy similar to the whole mitochondrial protein preparation.
Conclusions:
- TAMAs can elicit effective antitumor immune responses.
- Mitochondrial-derived antigens, particularly from mutated COX1, show promise for cancer immunotherapy.
- This approach offers a potential new strategy for treating cancer.
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