Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone.
Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone.
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线粒体靶向阿托瓦酮原位免疫预防肿瘤生长和扩散。
DOI：
10.1002/advs.202101267
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发表时间：
2022-04
期刊：
影响因子：
15.1
通讯作者：
You, Ming
中科院分区：
文献类型：
--
作者：
Huang, Mofei;Xiong, Donghai;Pan, Jing;Zhang, Qi;Wang, Yian;Myers, Charles R.;Johnson, Bryon D.;Hardy, Micael;Kalyanaraman, Balaraman;You, Ming
关键词：
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. 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.
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DOI：
10.1158/1940-6207.capr-20-0425
发表时间：
2021-03
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Huang M;Myers CR;Wang Y;You M
通讯作者：
You M
影响因子：
2.9
作者：
Freeman, CD;Klutman, NE;Strayer, AH
通讯作者：
Strayer, AH
影响因子：
10.1
作者：
Hossain, Fokhrul;Al-Khami, Amir A.;Ochoa, Augusto C.
通讯作者：
Ochoa, Augusto C.
影响因子：
29
作者：
Angelin A;Gil-de-Gómez L;Dahiya S;Jiao J;Guo L;Levine MH;Wang Z;Quinn WJ 3rd;Kopinski PK;Wang L;Akimova T;Liu Y;Bhatti TR;Han R;Laskin BL;Baur JA;Blair IA;Wallace DC;Hancock WW;Beier UH
通讯作者：
Beier UH
影响因子：
15.9
作者：
Gerriets, Valerie A.;Kishton, Rigel J.;Rathmell, Jeffrey C.
通讯作者：
Rathmell, Jeffrey C.