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Immune system tamer appears to also fuel cancer

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An innate enzyme that impairs immune response not only helps cancer evade the immune system but also appears to fuel its growth and spread, particularly in the lungs, researchers said.

Though the work was done in animals, it provides compelling evidence to look at inhibitors of the enzyme in human clinical trials, the researchers said.

Working with mice, researchers focused on an enzyme called indoleamine 2,3-dioxygenase, or IDO.

The enzyme attracted worldwide attention in 1998 when Georgia Health Sciences University researchers Andrew Mellor and David Munn showed it was part of the mechanism that protects a developing fetus and its foreign genetic material from the mother’s immune system.

They and others since have shown IDO is implicated in a number of other systems, including cancerous tumors that manipulate IDO to hide from the host’s immune system.

In a study published Thursday in the journal Cancer Discovery, Dr. Alexander J. Muller and colleagues show that IDO does far more than just help the tumor “escape” the immune system.

Mice bred to develop lung cancer tumors that lacked IDO survived longer than those that had the enzyme in abundance.

It turns out that those mice without IDO lacked the vascular growth in the lungs, “which was totally unexpected,” said Muller, an associate professor at the Lankenau Institute for Medical Research in Wynnewood, Pa.

“It had not been known or suspected that the IDO pathway would be involved in the blood vessel growth and that sort of basic growth of the tumor. That was really interesting,” said Munn, a pediatric oncologist and a researcher in the cancer immunotherapy program at GHSU. He has collaborated with Muller and some of his colleagues in the past but was not involved in the study.

The mice that lacked IDO had less spontaneous spread, or metastasis, of their cancer, which is important, Muller said.

“We wanted to look at metastases because metastatic disease is in large part the real problem with cancer,” he said.

IDO appeared to increase an important inflammatory protein called interleukin-6 that has been shown to help feed the growth of cancer and to recruit myeloid-derived suppressor cells that suppress the immune response to the tumors, another unexpected role for IDO, Muller said.

“It’s at this nexus between all of these different components that are so important for tumor development,” he said.

Said Munn: “Rather than simply making it invisible to the immune system so it doesn’t get destroyed, IDO appears to be playing a role in promoting (tumor) growth independent of the immune system.”

The study said the evidence presented should strongly encourage investigators to look at clinical trials of IDO inhibitors in lung cancer and lung metastases “where more effective (treatments) are urgently needed.”

Inhibitors of IDO are already being tested in early clinical trials, often in conjunction with other therapies, said Munn, who helped develop one inhibitor called 1-methyl tryptophan and also works as a consultant in some of the trials using the inhibitor.

“When I see something as fundamental as new blood vessel growth in a tumor, my first thought is that applies widely,” he said. “It is definitely true that we need novel therapies for lung cancer. That is a dreadful tumor, and we don’t have a lot of therapeutic options. I certainly think that people should be encouraged to look at IDO (inhibitors) in lung cancer.”


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