Metabolic inhibition of glutamate-cysteine ligase increases dendritic cell-mediated anti-tumor immunity in melanoma

In this study we used the transgenic melanoma mouse model tg(Grm1)EPv, which spontaneously develops melanoma due to the ectopic expression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes to investigate if aberrant glutamate metabolism drives tumor formation, and affects immune cell function.

LC-MS/MS-based metabolomic analyses and RNA sequencing revealed changes in glutaminolysis, a glycolytic shift (Warburg effect), and reduced ATP levels in advanced tumors compared with tumor free tissue, suggesting respiratory chain dysfunction. These metabolic changes in the TME are advantageous for the tumor cells and unfavorable for immune cells, such as dendritic cells (DC). Indeed, flow cytometry analysis of myeloid subsets during tumor progression showed a decline in tumor-infiltrating conventional type 2 dendritic cell (cDC2) and macrophages, alongside an increase in neutrophil and monocyte populations in advanced lesions.