Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria‐Targeted Atovaquone. Issue 12 (4th March 2022)

• Record Type: Journal Article
• Authors: Huang, Mofei; Xiong, Donghai; Pan, Jing; Zhang, Qi; Wang, Yian; Myers, Charles R.; Johnson, Bryon D.; Hardy, Micael; Kalyanaraman, Balaraman; You, Ming
• Is Part Of: Advanced science. Volume 9:Issue 12(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-03-04
• Subjects: in situ vaccination -- lung cancer -- mitochondria‐targeted atovaquone -- mitochondrial bioenergetics -- tumor immune microenvironment; Science -- Periodicals; 505
• DOI: 10.1002/advs.202101267
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: 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. Abstract : Mitochondria‐targeted atovaquone (Mito‐ATO) in situ vaccination eliminates tumor cells by activating systemic CD4 + T response through blocking both granulocytic‐myeloid‐derived suppressor cells (G‐MDSCs) and regulatory T cells (Tregs). Mito‐ATO inhibited complex I and glycolysis in G‐MDSCs and complex III in Tregs. Targeting G‐MDSCs and Tregs with Mito‐ATO is a promising approach to eradicate disseminated tumors.