Een functioneel single cell metabolisch onderzoek identificeert Elovl1 als een doelwit om de fitheid van CD8+ T-cellen in solide tumoren te verbeteren

Rationale: In the TME aberrant production of metabolites and a strong competition among cancer cells and stromal cells for limited nutrients prevail. Given the link between metabolism and T cell fitness, it is now clear that the functions and fate of T cells is altered in a way to favor immunological tolerance and reduce anti-tumor effector functions. This holds true even in the presence of therapeutic intervention that should promote effector T cell expansion and anti-tumor activity. Therefore, breaking the immune suppressive barrier of the TME by reprogramming the intrinsic metabolism of tumor-reactive T cells is emerging as whole new, yet unexplored, promising area of cancer immunotherapy. Aims: We are seeking to understand how to manipulate the metabolic state of T cells and increase T cell fitness bypassing the immunosuppressive properties of the TME linked to nutrient restriction and altered metabolites production. We will perform an in vivo high-throughput functional genomic screening to explore the metabolism of cytotoxic CD8+ T cells and identify metabolic targets able to increase their fitness in the harsh TME. The biology behind a selected number of identified genes will be dissected through a complete phenotypic characterization. Clinical and therapeutic relevance will then be endorsed by the use of several orthotopic metastatic models and preclinical evaluation of druggable targets in different antigen models. The ultimate goal is to build new leading-edge concepts into T cell metabolism to endorse CD8+ T cell fitness as a new therapeutic way for cancer treatment.