Effect of systemic depletion of glutamine via PEGylated glutaminase on CT26 tumor tissue.

Proliferating cancer cells are addicted to glutamine for biomass synthesis and energy generation. We here enzymatically deplete circulating glutamine in mice and report how cancer cells adapt to low circulating glutamine and document immunological changes in the tumor microenvironment (TME) upon glutamine depletion in CT26 tumor model. We show that cancer cells adapt to low glutamine by diverting intracellular glutamine flux to nucleotide synthesis and downregulating global translation. Through immune cell deconvolution and GSEA, we show that systemic glutamine depletion is immunsosuppressive and marked by accumulaton of PMN-MDSC in the TME. We implanted CT26 tumor in six BALB/c mice subcutaneously. When, the tumors were palpable, we treated three mice with 50 IU/kg PEGylated glutaminase and three with vehichle (PBS, 10% glycerol) every three days. After two treatmetns, we euthanized the mice, froze the tumor tissue and confirmed glutamine depletion in mouse serum.