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In many solid tumors, T lymphocytes are unable to move properly to reach cancer cells. This migration anomaly is one of the main reasons for the failure of current immunotherapies. Therefore, understanding the mechanisms involved in the migration of T lymphocytes is crucial for designing strategies that enhance this function.
Using dynamic imaging microscopy, which allows the tracking of cell movement, on ex vivo models, researchers highlighted the importance of metabolism in the intratumoral migration of T lymphocytes. The findings show that, unlike cancer cells, T cells do not rely on the energy released from sugar degradation in the cell cytoplasm (glycolysis) for movement.
Instead, they use energy from mitochondrial metabolism, which is produced in the form of adenosine triphosphate (ATP) at the cell's core. ATP therefore plays a decisive role in the migration of T lymphocytes. Further experiments identified, in addition to ATP, reactive oxygen species (ROS) produced by the mitochondria as key drivers of T cell mobility.
Enhancing T cell mobility within tumors
Using murine models in lung cancer studies, 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 genetically modified T lymphocytes expressing an antigen receptor. This receptor specifically recognizes cancer cells in order to destroy them (CAR-T cells). CAR-T cells with enhanced mitochondrial metabolism showed a better ability to make contact with tumor cells before eliminating them.
On the left, mitochondrial activity fueled by glucose and glutamine supports T cell migration through ATP and reactive oxygen species (ROS) production.
On the right, pharmacological approaches used during in vitro cultivation to enhance the mitochondrial metabolism of CAR-T cells enable these cells to actively migrate into tumors to reach tumoral islands and efficiently kill cancer cells.
© Creative Commons Attribution 4.0 International License. Luca Simula.
The results of this study provide new insights into how the tumor microenvironment hinders T lymphocyte movement. Furthermore, they could help optimize current immunotherapy strategies by targeting T cell metabolism to enhance T cell mobility.
Reference:
Simula L, Fumagalli M, Vimeux L, et al. Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors. Nat Commun. 2024;15(1):2203. Published 2024 Mar 11. doi:10.1038/s41467-024-46377-7.