Double Trouble: Tumors have two-pronged defense

To survive long enough to form a tumor, cancer cells must ward off attacks by the body’s immune system. Some cancers protect themselves by vacuuming up the amino acid tryptophan, which nearby immune system cells need in order to attack.

Now scientists have discovered that these cancer cells simultaneously pump a poison into their surroundings, killing those immune system cells when they get too close.

These two actions—soaking up tryptophan and dumping out the toxin—are intimately connected, the researchers found. Whenever a pore in the cancer-cell membrane lets in a tryptophan molecule, it ejects some other molecule, like two people passing through a revolving door in opposite directions. Usually, the expelled molecule is the poison.

“We show for the first time that these amino acid transporters are capable of exchanging these two molecules,” says lead scientist Thijs Kaper, now at the biotechnology company Genencor in Palo Alto, Calif. “The [toxin] is actually driving the uptake of more tryptophan, so it’s a cycle that keeps itself going.”

All cells create the proteins that they need by stringing together amino acids. Cells can manufacture some of these amino acids, but others—the so-called essential amino acids, including tryptophan—must be acquired from the cell’s surroundings.

The attack dogs of the immune system, killer T cells, are particularly sensitive to tryptophan scarcity. They need the amino acid to produce signaling proteins that switch the T cells to search-and-destroy mode. “Tryptophan seems to be one of the big choke points for controlling the immune response,” says Lawrence Steinman of Stanford University, a member of the research team.

In addition, notes Andrew L. Mellor of the Medical College of Georgia in Augusta, T cells stop multiplying when they sense low tryptophan concentrations. Mellor says that this control mechanism, normally used by the immune system to keep T cells in check, is one that some kinds of cancer cells appear to have hijacked.

Such cancer cells can continuously drain tryptophan from their surroundings. They contain an overactive form of a protein that breaks down the amino acid and converts it to kynurenine, which the cells expel. Completing the double whammy, from the cancer cells’ perspective, kynurenine kills nearby T cells.

To track concentrations of these two compounds in human-oral-cancer cells grown in the lab, Kaper’s team used a fluorescent molecule-sensing technology that the researchers had developed. When a sensor molecule binds to one of the two compounds, the light it emits changes color. By monitoring the color fluctuations under a microscope, the team was able to measure changes in the concentrations of these compounds as they occurred.

The scientists showed that tryptophan enters cells through a specialized pore called L-amino acid transporter 1 (LAT1) and that as tryptophan moves in, the molecule that moves out is most often kynurenine. LAT1 enforces a “one in, one out” policy, the team reports in the October PLoS Biology.

“I think it’s an important step in understanding the underlying biochemistry of how cancer cells control the immune response,” Mellor comments.

From the Nature Index

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