Genetically Engineering Metabolic Pathways in T-Cells to increase their anti-tumor function

T-cells are central to the anti-tumor response though they encounter several hurdles in the tumor microenvironment such as the lack of available essential metabolites (e.g., glucose, amino acids…). Moreover, cancer cells can monopolize some of these resources to survive and proliferate by driving a higher expression of metabolite transporters, maintaining a high metabolic rate and thereby, outcompeting T cells. To improve T-cell anti-tumor function in the tumor vicinity, we aimed at endowing T-cells with some tumor characteristics such as the overexpression of genes involved in metabolic pathways. In this work, we focused on the overexpression of glucose transporters or key enzymes in glycolysis pathways and showed that this approach can substantially enhance T-cell function. We co-transduced these genes along with tumor-specific T-cell receptors, namely the F5 TCR specific for the MART1 antigen and CD19-specific CAR. T-cells expressing TCR/CAR, along with selected metabolic genes could demonstrated a higher anti-tumor potential by means of cytokines secretion, activation marker expression and cytotoxicity in co-cultures with cognate tumor cells. Additionally, we analyzed their immunophenotype and noted an increase in mitochondrial mass and glycolysis rate. Finally, metabolically enhanced T-cells demonstrated an improved in-vivo function in a xenograft model of human tumor in mice. In conclusion, T cells can be genetically modified to express metabolism-related genes which will contribute to the improvement of engineered T cell-based immunotherapy.