Journal
ADVANCED SCIENCE
Volume 9, Issue 12, Pages -Publisher
WILEY
DOI: 10.1002/advs.202101267
Keywords
in situ vaccination; lung cancer; mitochondria-targeted atovaquone; mitochondrial bioenergetics; tumor immune microenvironment
Categories
Funding
- National Institutes of Health [R01CA223804, R01CA232433, R01CA205633]
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Mitochondria-targeted atovaquone inhibits the expression of genes involved in oxidative phosphorylation and glycolysis, leading to the death of granulocytic-myeloid-derived suppressor cells and regulatory T cells. This treatment also increases tumor-infiltrating CD4(+) T cells and improves the anti-tumor activity of PD-1 blockade immunotherapy.
Atovaquone, an FDA-approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria-targeted atovaquone increased mitochondrial accumulation and antitumor activity in vitro. Using an in situ vaccination approach, local injection of mitochondria-targeted atovaquone into primary tumors triggered potent T cell immune responses locally and in distant tumor sites. Mitochondria-targeted atovaquone treatment led to significant reductions of both granulocytic myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. Mitochondria-targeted atovaquone treatment blocks the expression of genes involved in oxidative phosphorylation and glycolysis in granulocytic-myeloid-derived suppressor cells and regulatory T cells, which may lead to death of granulocytic-myeloid-derived suppressor cells and regulatory T cells. Mitochondria-targeted atovaquone inhibits expression of genes for mitochondrial complex components, oxidative phosphorylation, and glycolysis in both granulocytic-myeloid-derived suppressor cells and regulatory T cells. The resulting decreases in intratumoral granulocytic-myeloid-derived suppressor cells and regulatory T cells could facilitate the observed increase in tumor-infiltrating CD4(+) T cells. Mitochondria-targeted atovaquone also improves the anti-tumor activity of PD-1 blockade immunotherapy. The results implicate granulocytic-myeloid-derived suppressor cells and regulatory T cells as novel targets of mitochondria-targeted atovaquone that facilitate its antitumor efficacy.
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