Researchers identify immune dysfunction in melanoma patients

Researchers at the Stanford University School of Medicine have begun to shed light on why the human immune system isn't able to stop such cancers as melanoma, suggesting answers that could pave the way for better treatment of this often-fatal illness.

In a small study, the scientists found that the immune cells in a majority of people with this deadly skin cancer fail to respond properly to a molecule called interferon, which normally activates the immune system. Without the ability to respond to interferon, the cells are less able to fend off the cancer, according to the study that will be published in the May issue of Public Library of Science-Medicine.

These results help explain a decade of research showing that people with cancer often have dysfunctional immune systems. Until now, researchers could tell that the immune system wasn't working properly but didn't know which genes or pathways were involved in that failure. Finding the disruption in the cancer cells' interferon response could help in the development of vaccines to treat cancers.

"We think this is a dominant way that immune dysfunction occurs in people with cancer," said senior author Peter Lee, MD, associate professor of medicine.

Lee was interested in melanoma rather than other forms of cancer in part because of the deadly nature of the disease, which will kill about one in six of the 47,700 people it is expected to strike this year. Unless melanoma is caught early and removed, there is no effective treatment, although research groups have been testing vaccine therapies for the disease. However, Lee worried that unless researchers better understood immune dysfunctions in those people, the vaccines would have a low probability of success. "If you don't address the underlying immune defects, then vaccines won't do any good," Lee said.

The group started by separating out the four major types of immune cells from people with melanoma and from healthy people. These cells were B cells, two types of T cells and NK, or natural killer, cells. Then, postdoctoral scholar Rebecca Critchley-Thorne, PhD, lead author of the paper, looked in the immune cells of healthy people vs. those with melanoma to see if they had the same levels of activation of roughly 20,000 genes.

She found that the B cells and both types of T cells in people with melanoma showed activity levels that differed from healthy people in only 25 of those genes. Seventeen of those 25 were normally turned on in response to interferon.

"Interferon normally acts as a critical signal in activating immune cells," said Critchley-Thorne. Without the ability to respond to interferon, those cells might detect the cancer but won't activate properly.

This type of experiment only shows that certain genes are turned on at different levels in people with melanoma. It doesn't prove that the cells behave differently than the immune cells of normal people. To verify that the interferon signaling was defective in people with melanoma, Critchley-Thorne isolated those cells and exposed them to interferon.

As predicted, immune cells from people with melanoma also failed to respond normally to the immune activation signal. However, she found that if she left the cells in the presence of a high dose of interferon for much longer than would normally be required, those cells did begin responding.

Lee said the finding explains why a common melanoma treatment, in which some doctors have treated patients with prolonged exposure to interferon, sometimes helps. "Doctors knew it worked in some people but didn't know why," Lee said. This data suggests that treatment works by overcoming the immune system's inability to react properly to interferon.

If Lee's suspicion turns out to be true, doctors may be able to screen melanoma patients for interferon response and provide prolonged interferon treatment for only those patients whose immune cells have defects in that pathway. That means patients who wouldn't benefit from the treatment could avoid suffering through interferon's flu-like side effects.