TY - JOUR
T1 - Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone
AU - Huang, Mofei
AU - Xiong, Donghai
AU - Pan, Jing
AU - Zhang, Qi
AU - Wang, Yian
AU - Myers, Charles R.
AU - Johnson, Bryon D.
AU - Hardy, Micael
AU - Kalyanaraman, Balaraman
AU - You, Ming
N1 - Funding Information:
M.H., D.X., and J.P. contributed equally to this work. This work was supported by the grants from the National Institutes of Health (R01CA223804, R01CA232433, R01CA223804, and R01CA205633).
Publisher Copyright:
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
PY - 2022/4/25
Y1 - 2022/4/25
N2 - 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.
AB - 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.
KW - in situ vaccination
KW - lung cancer
KW - mitochondria-targeted atovaquone
KW - mitochondrial bioenergetics
KW - tumor immune microenvironment
KW - Atovaquone/metabolism
KW - Mitochondria/metabolism
KW - Humans
KW - Vaccination
KW - Oxidative Phosphorylation
KW - Tumor Microenvironment
KW - Neoplasms
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U2 - 10.1002/advs.202101267
DO - 10.1002/advs.202101267
M3 - Article
C2 - 35243806
AN - SCOPUS:85125564839
VL - 9
SP - e2101267
JO - Advanced Science
JF - Advanced Science
SN - 2198-3844
IS - 12
M1 - 2101267
ER -