In many solid tumors, T lymphocytes are unable to migrate properly to reach cancer cells. This migration defect is one of the main reasons why current immunotherapies fail. There is therefore an urgent need to understand the mechanisms involved in T cell migration, in order to devise strategies to enhance this function.
Using dynamic imaging microscopy, which tracks the movement of cells, in ex vivo models, the researchers highlighted the importance of metabolism in T cell intratumoral migration. The results show that, unlike cancer cells, T cells do not use the energy released by the breakdown of sugar in the cell cytoplasm (glycolysis) to move. Instead, they use energy from mitochondrial metabolism, which is produced at the heart of the cell in the form of adenosine triphosphate (ATP). ATP thus plays a decisive role in T cell migration. In addition to ATP, other experiments have identified reactive oxygen species (ROS) produced by mitochondria as the driving force behind T cell mobility.
Using mouse models of lung cancer, the authors also demonstrated that it was possible to increase T cell infiltration into tumors by boosting their mitochondrial metabolism through pharmacological approaches. This strategy was then applied to an immunotherapy based on the use of T lymphocytes, genetically modified to express an antigen receptor. This receptor specifically recognizes cancer cells and destroys them (CAR-T cells). CAR-T cells with increased mitochondrial metabolism showed a greater ability to make contact with tumor cells before eliminating them.
The results of this study provide new insights into how the tumor microenvironment hinders T cell movement. They may also help optimize current immunotherapy strategies by targeting T cell metabolism to enhance T cell motility.
Figure legend: Left: Glucose- and glutamine-fueled mitochondrial activity supports T-cell migration via the production of ATP and reactive oxygen species (ROS). On the right, pharmacological approaches used during in vitro culture to increase mitochondrial metabolism in CAR-T cells enable these cells to actively migrate into tumors in order to reach tumor islets and effectively kill cancer cells.
Reference
Simula, L., Fumagalli, M., Vimeux, L., Rajnpreht, I., Icard, P., Birsen, G., An, D., Pendino, F., Rouault, A., Bercovici, N., Damotte, D., Lupo-Mansuet, A., Alifano, M., Alves-Guerra, M. C., & Donnadieu, E. (2024, Mar 11). Mitochondrial metabolism sustains CD8(+) T cell migration for an efficient infiltration into solid tumors. Nat Commun, 15(1), 2203. https://doi.org/10.1038/s41467-024-46377-7
