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.

Tumor biologists in the Department of Colorectal Cancer at Zhejiang University School of Medicine in Hangzhou, China, found in both animal models and human cancers that specific amino acids predominate in crucial cancer-cell survival strategies. For example, increased usage of the amino acid arginine aided rapid tumor progression, while reduced metabolism of another amino acid, lysine, prevented the activation of cytotoxic T cells, commonly known as killer T cells. The research is reported in the journal Science Immunology.

“Our study highlights an amino acid trade-off that dynamically optimizes the metabolic preferences of tumors to promote proliferation and immune evasion,” writes Dr. Weiwei Yu, lead author of a multipronged investigation that explored the metabolic adaptations that alter the tumor microenvironment and potentially boost the growth of tumors.

Shifting the metabolic landscape

Although scientists have been aware for decades of various tactics that malignant cells employ to ensure their survival, the impact of dual amino acid activities on tumor progression and antitumor immunity has remained somewhat cloudy. The new research adds a clearer perspective by demonstrating that arginine and lysine metabolism are substantially altered to support the growth and survival of the tumor.

Earlier research suggested that cancer cells can control the availability of amino acids in the tumor microenvironment, but it was not obvious what effects lysine and its metabolites had on tumors and immune cells.

Seeking clarity, Yu and colleagues analyzed tumor microenvironment metabolite levels in human cancers and mouse models of cancer. Their analyses revealed that tumor cells increased expression of the gene SLC7A1, which promotes arginine uptake and utilization. This metabolic shift supported tumor growth.

By contrast, tumor cells downregulated—decreased—expression of the gene SLC7A2, which reduced lysine uptake and breakdown. This lowered levels of the lysine metabolite glutaconic acid in the tumor microenvironment. That single action promoted immune evasion because it became easier for tumors to avoid the immune system’s killer T cells.

Driving proliferation and evasion

“Tumor cells promote metabolic dysregulation of immune cells by controlling the metabolic landscape of the tumor microenvironment,” Yu noted in the study. “It is unclear whether tumors restrict specific nutrients to drive rapid growth and immune evasion in addition to the overconsumption of nutrients to support anabolism.”

The repression of lysine catabolism in tumor cells, for example, caused the decline of a lysine breakdown product, glutaconic acid, which created a major problem, the team found, because the acid stimulates antitumor CD8 T cells.

Inhibiting the ability of killer T cells to conduct surveillance and destroy tumor cells allowed the malignancy to create the equivalent of Harry Potter’s invisibility cloak. Evading the immune system benefited tumor growth and proliferation, Yu and colleagues discovered.

The team also reported finding unequivocal evidence that cancers are simultaneously capable of tumor progression and immune evasion via amino acids because malignant cells are fully equipped to commandeer the metabolic activities of arginine and lysine.

A full arsenal of survival tactics

Along with the role of the two amino acids highlighted in the research by Yu and colleagues, scientists have long known of other strategies that tumors employ to sustain their growth and survival.

Studies dating back decades by the late Harvard University researcher Judah Folkman revealed that the process of angiogenesis—blood vessel development—allows tumors to tap into the host’s blood supply to gain nutrients. Tumors often grow along host blood vessels, which can be hijacked by cancers.

Other methods of securing survival at the expense of normal host cells include resisting apoptosis—cell death—and jamming signals that host cells need to function properly. Tumor cells can also mimic or clone these signals to produce their own growth factors.

As it turns out, cancer growth demands an extraordinary amount of cellular fuel, creating an environmental crisis for tissues surrounding a tumor. And it is within the high-stress microenvironment—where the energy demands are made—that the amino acid trade-off discovered by Yu and colleagues operates.

By altering cellular chemistry to simultaneously upregulate arginine and choke off lysine breakdown, the team demonstrated that tumors do more than just feed their own out-of-control switches. They actively deplete the microenvironment of immunostimulatory byproducts like glutaconic acid, effectively blinding the host’s key defense forces before an attack can even begin.

Yet, the story of arginine and lysine isn’t one in which tumors hold all of the power. The team also discovered that when glutaconic acid levels were increased, there was greater CD8 T cell infiltration in patients with colorectal cancer. In addition, patients who had higher lysine metabolism levels showed better responses to immune checkpoint therapy, Yu and team members found.

Similarly, supplementing immune checkpoint therapy with glutaconic acid in mouse models of cancer improved treatment efficiency. Yu speculated in the study that targeting lysine metabolism and glutaconic acid could improve future immunotherapeutic outcomes for patients undergoing treatment for cancer.

Who’s behind this story?

Delthia Ricks

Award-winning science writer published in Newsday and Discover Magazine. Author of four books. UCLA and Columbia graduate.

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Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Robert Egan

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