Tumor Vs. Immune System: How Proteins Tip the Balance

The immune system has long been in the crosshairs of cancer researchers, as it plays a central role in defending the human body from foreign invasion. In a study published today in Journal of Experimental Medicine, researchers from the University of Tsukuba have revealed that tumors that produce a protein called soluble CD155 accumulate in the lungs of mice by disabling the immune system of the animals.

Soluble CD155 is a protein that is made by many different cells in the body and plays an important role in how cells migrate and develop. Surprisingly, several studies by the group at the University of Tsukuba have shown that higher serum levels of soluble CD155 can be found in patients with various types of cancer.

“Correlation does not imply causation,” says senior author Kazuko Shibuya. “We wanted to know specifically how soluble CD155 is involved in the growth of cancer.”

CD155 has been shown to bind to the proteins DNAM-1, TIGIT, and CD96, all of which are expressed by various types of immune cells. To achieve their goal, the researchers changed the B16/BL6 melanoma cells to produce soluble CD155. When injected into either normal mice or mice that are deficient in TIGIT or CD96, the soluble CD155-producing B16/BL6 cancer cells were able to settle and grow in their lungs. Quite the opposite happened, however, when the same experiment was performed with mice deficient in DNAM-1; the researchers could not find a larger tumor in the lungs of the animals.

“Our results show that DNAM-1 was somehow involved in the tumor-promoting actions of soluble CD155,” says first author Genki Okumura. “Our next goal was to explore further how the two proteins interact to enable the growth of cancer.”

The researchers depleted natural killer (NK) cells in the mice and found that all differences between them disappeared. In further experiments, they found that soluble CD155 prevented NK cells from releasing small proteins that are toxic to cancer cells by binding to DNAM-1.

“These are striking results that show how a single protein can drastically change the fate of a tumor,” Shibuya says. “Targeting soluble CD155 could therefore be a new powerful strategy to treat cancer.”