News - Prévention de la croissance tumorale et de la propagation par vaccination in situ avec une atovaquone ciblant les mitochondries

Prévention de la croissance tumorale et de la propagation par vaccination in situ avec une atovaquone ciblant les mitochondries

L’atovaquone, un médicament utilisé pour traiter le paludisme, est connu pour inhiber la chaîne de transport électronique mitochondriale. Dans cette étude, nous avons développé un nouvel agent dérivé de l’atovaquone ciblant les mitochondries (Mito-ATO). Cette molécule s’accumule dans les mitochondries de cellules cancéreuses ainsi que dans les cellules immunosuppressives au sein du microenvironnement immunitaire tumorale (TIME). En utilisant une approche de vaccination in situ, l’injection de Mito-ATO dans les tumeurs primaires a déclenché de puissantes réponses immunitaires des lymphocytes T en local mais aussi dans des sites tumoraux distants.

Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone

Huang Mofei, Xiong Donghai, Pan Jing, Zhang Qi, Wang Yian, Myers Charles R., Johnson Bryon D., Hardy Micael, Kalyanaraman Balaraman, You Ming
Advanced Science, 9 2101267 (2022)

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.

Collaborations :

Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226 USA

https://www.mcw.edu/departments/biophysics/people/balaraman-kalyanaraman-PhD

Center for Cancer Prevention, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX, 77030 USA.

https://you.hmailabs.org

Financial supports:

-NIH, Grant ID: R01CA232433; NIH, Grant ID: R01CA205633; NIH, Grant ID: R01CA223804

Aix Marseille université, CNRS