Single-Cell Characterization of the Dynamics of T-cell Metabolism during the Immune Response: Enhancing Current Immunotherapies by Boosting Immune-Cell Metabolic Fitness in the Tumor Microenvironment

The immune system constitutes our body’s defensive barrier against pathogens and tumors. T cells are at the forefront of this barrier, providing immediate and long-term (memory) protection against those threats. When a virus or tumor arises in the body, T cells dynamically evolve from a resting to an activated state, in which they can rapidly proliferate and release agents to kill the infecting or tumor cells. To support the different stages of this dynamic response, T cells in turn need to feed on specific nutrients from their environment. The metabolism of T cells is thus highly dynamic, and the ability of T cells to provide an optimal protection relies on the availability of appropriate nutrients at each of the stages of this response. Yet, the specific nutrients on which T cells depend the most at each of those stages are still unknown. This knowledge is particularly important in the case of the anti-tumor immune defense, as tumor cells actively modulate their nutrient environment to evade the immune response. In my project, I will characterize the dynamic metabolic requirements of T cells evolving down the immune response cascade, using a novel approach based on single-cell RNA-sequencing. Specifically, I will identify which of those requirements cannot be adapted under conditions reflecting those found within the nutrient-restricted environment of a tumor, and use this information to devise strategies to boost the effectiveness of current anti-tumor immunotherapies.