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Vaccination: targeting mitochondria to prevent tumours

Atovaquone, a drug used to treat malaria, is known to inhibit the mitochondrial electronic transport chain. In this study, conducted in France by researchers at the Institut de chimie radicalaire (CNRS / Aix-Marseille Université), a new mitochondria-targeting agent derived from atovaquone (Mito-ATO) was developed to prevent tumor growth and spread.

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Key points to remember:

  • The researchers suggest using a derivative of the antimalarial drug atovaquone, called Mito-ATO, to prevent the growth and spread of tumors.
  • In cancer, immunosuppressive cells called g-MDSCs and Tregs multiply around tumors. Mito-ATO injected by vaccination attacks not only tumors, but also these tumor immune cells.
  • This mode of action against these new targets (g-MDSCs and Tregs) represents an innovative means of regulating tumor immunity, in order to effectively prevent and treat cancers and their metastases.

Vaccinating mitochondria in cancer?

Mito-ATO vectorization increases its accumulation in the mitochondria of cancer cells, as well as in immunosuppressive cells within the tumor immune microenvironment (TIME). These populations of so-called immunosuppressive cells, such as myeloid suppressor cells (g-MDSCs) and regulatory T lymphocytes (Tregs), are amplified in pathological situations such as cancer, hence the need to reduce their numbers.



Using an in situ vaccination approach, injection of Mito-ATO into primary tumors triggered potent T cell immune responses locally, but also at distant tumor sites. As demonstrated in transplantable tumor models and in a spontaneous tumor model, this immune response also led to the attack of tumor cells in localized foci in different parts of the body. In situ vaccination with Mito-ATO prevents the spread of lung cancer metastases and their development in the brain. In addition, flow cytometry analysis revealed that treatment with Mito-ATO led to a significant reduction in g-MDSCs as well as Treg lymphocytes in TIME.

Mito-ATO: antitumor properties that treat cancer and metastases

Single-cell transcriptomics (scRNA-seq) showed that Mito-ATO treatment blocks expression of genes responsible for oxidative phosphorylation (OXPHOS) and glycolysis in g-MDSCs and Tregs cells. This would lead to cell death of these cells within the tumor microenvironment, explaining the decrease observed with Mito-ATO treatment.



Mito-ATO inhibits the expression of complex I, V, OXPHOS and glycolysis genes in g-MDSCs cells, and the expression of complex I, III, IV, OXPHOS and glycolysis genes in Tregs cells. The intratumoral decrease in g-MDSCs and Tregs could facilitate the observed increase in tumour-infiltrating CD4+ T cells. These results highlight the anti-tumor efficacy of Mito-ATO on novel TIME targets (g-MDSCs and Tregs).



The strategy of targeting g-MDSCs and Tregs with Mito-ATO is therefore an innovative and attractive approach to regulating tumor immunity in order to effectively prevent and treat cancers and their metastases.

Nom
Hardy
Micael
Fonction
Senior Lecturer at the Institut de chimie radicalaire (CNRS / Aix-Marseille Université)

Reference: Huang, M., Xiong, D., Pan, J., Zhang, Q., Wang, Y., Myers, C. R., Johnson, B. D., Hardy, M., Kalyanaraman, B., You, M., Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone. Adv. Sci. 2022, 2101267.

Published March 4 in Advanced Science.

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