Crosstalk between arginine, glutamine, and the branched chain amino acid metabolism in the tumor microenvironment

Abstract

Arginine, glutamine, and the branched chain amino acids (BCAAs) are a focus of increased interest in the field of oncology due to their importance in the metabolic reprogramming of cancer cells. In the tumor microenvironment (TME), these amino acids serve to support the elevated biosynthetic and energy demands of cancer cells, while simultaneously maintaining the growth, homeostasis, and effector function of tumor-infiltrating immune cells. To escape immune destruction, cancer cells utilize a variety of mechanisms to suppress the cytotoxic activity of effector T cells, facilitating T cell exhaustion. One such mechanism is the ability of cancer cells to overexpress metabolic enzymes specializing in the catabolism of arginine, glutamine, and the BCAAs in the TME. The action of such enzymes supplies cancer cells with metabolic intermediates that feed into the TCA cycle, supporting energy generation, or providing precursors for purine, pyrimidine, and polyamine biosynthesis. Armed with substantial metabolic flexibility, cancer cells redirect amino acids from the TME for their own advantage and growth, while leaving the local infiltrating effector T cells deprived of essential nutrients. This review addresses the metabolic pressure that cancer cells exert over immune cells in the TME by up-regulating amino acid metabolism, while discussing opportunities for targeting amino acid metabolism for therapeutic intervention. Special emphasis is given to the crosstalk between arginine, glutamine, and BCAA metabolism in affording cancer cells with metabolic dominance in the TME.

Metabolic remodeling by the PD-L1 inhibitor BMS-202 significantly inhibits cell malignancy in human glioblastoma

“…2D ). Previous reports have shown a close relationship among arginine, glutamine, and BCAA metabolism in cancer cells [ 18 , 19 ], thus, we chose L-isoleucine, one of the BCAA metabolites, as our main focus. Interestingly, the results from ELISA assays showed that the content of L-isoleucine was dramatically decreased in BMS-202 treated group when compared to the control group (Fig.…”

Largescale multicenter study of a serum metabolite biomarker panel for the diagnosis of breast cancer

“… 29 , 30 , 31 Under normal physiological conditions, glutamate can convert to other non-essential amino acids through transamination. 23 , 32 Glutamate is also the precursor for glutathione, an antioxidant that acts as a free radical scavenger and antidote in cells. 33 Glutamate is an excitatory neurotransmitter that transmits signals in the central nervous system by binding to different types of receptors.…”

Metabolic Heterogeneity, Plasticity, and Adaptation to “Glutamine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase—ω-Amidase (Glutaminase II)] Pathway

“…Cancer cells exert significant control over the TME and thus can exhaust T-cell surveillance by limiting nutrient availability, releasing immunosuppressive cytokines, or creating a hypoxic environment. As noted, cancer cells and immune cells exhibit high demands for glutamine, arginine, and BCAAs to sustain growth and proper functioning [ 262 , 263 ]. Thus, inhibiting transport or utilization of these essential nutrients would be detrimental to metabolism of both cancer cells and cytotoxic T-cells.…”