PNAS mouse study claims interferon pathway might conceal a general immune defect in many cancer types.

Scientists at Stanford University’s School of Medicine have shown that muting a key voice in the conversation between human immune cells as they coordinate an effort to fight off infection is an early step in the progression of human cancers.

“Whatever functional defect these immune cells have likely impacts the effectiveness of both active immunotherapy, like cancer vaccines, and passive immunotherapy, like cellular therapies,” says Peter P. Lee, M.D., associate professor of hematology at the school of medicine. “If these forces are still at play in vivo, the patient’s immune response to these types of treatments will be blunted.”

The study, published May 18 in the Proceedings of the National Academy of Sciences, shows that the interferon pathway may harbor a general immune defect in many kinds of cancer. That may help explain the immune dysfunctions seen in numerous cancer patients, and why cancer immunotherapies are often ineffective.

The researchers are working with mice to pinpoint what exactly is going haywire in the pathway and why. They are also investigating whether the problems are likely to block the effectiveness of some of the newer immunotherapies that rely on the presence of a functional immune system.

Investigators artificially disrupted the pathways in mice. These animals develop spontaneous tumors at higher rates than normal animals with functional interferon signaling, which shows that the immune system eradicates many cancers in their infancy. “It’s a very dynamic interaction,” said Dr. Lee. “If the immune system is successful in stopping a developing cancer, we never know about it because no disease develops. If the cancer cell population overcomes the immune system, you get cancer.”

Dr. Lee and his colleagues had previously shown that the interferon signaling pathway was compromised in melanoma patients. In the current study, the team investigated whether patients with breast and gastrointestinal cancer also showed the same defect. They isolated lymphocytes in blood samples from patients with three types of cancers (32 breast cancer patients, 12 melanoma patients, and 11 gastrointestinal cancer patients) as well as from 28 age-matched healthy patients.

They then compared the response of three classes of lymphocytes—B cells, T cells, and NK cells—to exposure to interferons. The researchers found that lymphocytes from all types of cancer patients expressed significantly lower levels of interferon-responsive signaling molecules than did lymphocytes from healthy patients.

The team also found that the defect was equally severe in samples from people with early- and late-stage cancers—indicating that the problem must arise soon after the cancer begins to develop—and that it was present regardless of whether the patient had ever been treated with chemotherapy.

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Researchers Link Interferon Signaling to Immune Failure in Cancer Patients (5/8/2007)

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