Immunotherapy is a promising potential treatment for cancer, but it still has kinks to iron out. In a new study from Yale, researchers have identified a “jamming signal” that cancer uses to hide from the immune system – and importantly, engineered a synthetic immune protein that can fight back.
The natural version of this immune protein is called interleukin-18 (IL-18), and it’s just one weapon of many that the immune system deploys. Specifically, IL-18 is known to rally T cells and natural killer cells to fight off infections, as well as diseases like cancer. As such, it’s been investigated as a potential cancer treatment, but unfortunately it showed no real benefits in clinical trials.
“This was a major paradox to us because IL-18 sends an incredibly powerful inflammatory message to the ‘right’ immune cells that attack tumors,” says Aaron Ring, senior author of the study. “The fact that there was no response to natural IL-18 in previous clinical trials made us think that tumors were employing immunological countermeasures.”
So the researchers set out to investigate what these countermeasures might be – and they found one. Usually, IL-18 activates immune cells by binding to a receptor on their surface. But the team found that many types of cancer express a high amount of a protein called interleukin-18 binding protein (IL-18BP). As the name suggests, this also binds to IL-18, preventing it from activating the other immune cells. In that way, IL-18BP acts like a kind of decoy receptor.
With that mechanism in mind, the team then examined how they might be able to bypass it. They used a process called directed evolution, which mimics natural selection to guide proteins towards desired traits – in this case, those that ignore the decoy and only bind to the real receptor. After searching through around 300 million variations of IL-18, the researchers eventually found just what they were looking for.
The team then tested their new version of IL-18 on mice with a range of different tumor types. Sure enough, it slowed the growth of the tumors, and in many mice even managed to completely wipe out the cancer.
On closer inspection, the researchers saw that the synthetic IL-18 boosted the number of “stem-like” T cells that fight off cancer over extended periods. This technique could prove particularly useful against “cold” tumors that don’t invoke inflammation, which is a sign of immune activity.
“Because IL-18 can act on cells of the ‘innate’ immune system such as natural killer cells, it has potential to be effective against ‘cold tumors’ that have become resistant to conventional immunotherapies,” says Marcus Bosenberg, co-author of the study. “This is a major unmet need and one that the IL-18 pathway is poised to address.”
The team hoes to begin clinical trials of drugs based on the new synthetic immune protein next year.
The research was published in the journal Nature.
Source: Yale University
