Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone. Adv Sci (Weinh) 2022 Apr;9(12):e2101267
Date
03/05/2022Pubmed ID
35243806Pubmed Central ID
PMC9036031DOI
10.1002/advs.202101267Scopus ID
2-s2.0-85125564839 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
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.
Author List
Huang M, Xiong D, Pan J, Zhang Q, Wang Y, Myers CR, Johnson BD, Hardy M, Kalyanaraman B, You MAuthors
Micael Joel Hardy PhD Visiting Assistant Professor in the Biophysics department at Medical College of WisconsinBryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AtovaquoneHumans
Mitochondria
Neoplasms
Oxidative Phosphorylation
Tumor Microenvironment
Vaccination
