Fighting cancer: remodeling the tumor microenvironment

Studying the tumour immune microenvironment

Tumours are defined by the sum of a tumour microenvironment and tumour cells. The reprogramming of immune cells within the tumour immune microenvironment (TIME) contributes to cancer development, progression and metastasis. Immune cells with immunosuppressive functions play a key role in oncogenesis and rely on mitochondria to maintain their energy production and growth.

Atovaquone (ATO), a drug used to treat malaria, is known to inhibit the mitochondrial respiratory chain. Researchers have recently developed a mitochondria-targeted derivative of atovaquone (Mito-ATO) that inhibits the mitochondrial respiratory chain and anti-tumour activity in vivo. Using an in situ vaccination approach, local injection of Mito-ATO into primary tumours triggered potent T-cell immune responses locally and at distant tumour sites.

To study TIME, the researchers sequenced the RNA of immune cells from mice with lung tumours, treated with or without Mito-ATO, making it possible to map the different types of immune cells present in TIME. They found that treatment with Mito-ATO led to a significant reduction in the proportion of depleted CD8- T lymphocytes and an increase in the proportion of effector ("anti-tumour") memory CD8- T lymphocytes, which will be able to fight any recurrence. Mito-ATO also over-expresses genes involved in the recruitment of CD8+ T lymphocytes.

Enhancing anti-tumour immune cells

The metabolic activity studied within TIME showed that Mito-ATO significantly overexpressed oxidative phosphorylation (OXPHOS) activity in four populations of anti-tumour immune cells and suggested that this treatment could induce the differentiation of infection-fighting CD8+ T lymphocytes. In contrast, Mito-ATO significantly decreased OXPHOS activity in five pro-tumour immune cell populations.

Similarly, the key metabolic reactions of the Krebs cycle and glutaminolysis, which create energy for the cells, were intensified in anti-tumour immune cell populations, whereas they were reduced in pro-tumour immune cell populations.

Treatment with Mito-ATO also improves energy metabolism and suppresses cell death in anti-tumour immune cells, enabling them to fight cancer for longer. At the same time, Mito-ATO inhibits energy metabolism and promotes cell death in pro-tumour immune cells.

Finally, Mito-ATO has the ability to kill tumour cells directly by inhibiting tumour cell respiration, but also to promote anti-cancer immunity in the lung by remodelling the tumour microenvironment and improving the energy metabolism of anti-tumour immune cells.

Mito-ATO: a considerable clinical potential

Overall, we can therefore note that the use of Mito-ATO shuffles the cards with regard to lung cancer by promoting the proliferation and action of anti-tumour cells, while reducing the action of protumour cells.  The metabolic plasticity induced by Mito-ATO treatment could well contribute to the overall efficacy of this drug against lung tumours.

The Mito-ATO analogue, atovaquone, is already being tested in cancer clinical trials. As Mito-ATO is much more potent against human cancer cell lines than ATO, it is reasonable to predict that Mito-ATO has considerable clinical promise, alone and/or in combination with radiation or immunotherapy.

This work is the fruit of a long collaboration, recently supported by the CNRS IRP program (SuperO2) and bringing together researchers from the Institut de Chimie Radicalaire (ICR, Aix Marseille Université/CNRS), the Medical College of Wisconsin and the Houston Methodist Research Institute.