Fueling growth, blinding immunity: The two-way amino acid trap inside tumors
Tumors possess myriad mechanisms to ensure their survival even at the peril of the host. Now scientists are delving deeper into how cancer cells alter the metabolism of specific amino acids to support the malignancy's growth while simultaneously evading the antitumor activity of the host's immune system.
Tumors employ complex survival strategies that involve altering the metabolism of specific amino acids to fuel their growth while simultaneously evading the immune system. Researchers from Zhejiang University School of Medicine in China have identified a dual amino acid trap inside tumors that optimizes their metabolic preferences to promote proliferation and immune evasion.
Increased arginine usage supports rapid tumor progression, while reduced lysine metabolism prevents the activation of cytotoxic T cells, also known as killer T cells. The study, published in Science Immunology, emphasizes the dynamic optimization of tumor metabolic preferences to enhance growth and immune suppression. Previous research hinted at the impact of amino acid manipulation on tumor progression and antitumor immunity, but this new investigation provides a clearer understanding of the role of arginine and lysine metabolism.
The findings reveal that tumors increase the expression of the SLC7A1 gene, which promotes arginine uptake and utilization, supporting tumor growth. Conversely, tumors downregulate the SLC7A2 gene, reducing lysine uptake and breakdown, leading to lower levels of the lysine metabolite glutaconic acid. This decrease in glutaconic acid aids immune evasion by making it easier for tumors to avoid killer T cells.
By controlling the metabolic landscape of the tumor microenvironment, tumors actively deplete the area of immunostimulatory byproducts like glutaconic acid, effectively "blinding" the host's key defense forces. The study also discovered that increasing glutaconic acid levels leads to greater CD8 T cell infiltration in patients with colorectal cancer and improves treatment efficiency with immune checkpoint therapy.
The researchers speculate that targeting lysine metabolism and glutaconic acid could improve future immunotherapeutic outcomes for cancer patients undergoing treatment.
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