Disruption of Immune-System Pathway Key Step in Cancer Progression, Stanford Study Shows

STANFORD, Calif.--(Business Wire)--
Human immune cells communicate constantly with one another as they coordinate to
fight off infection and other threats. Now researchers at Stanford University`s
School of Medicine have shown that muffling a key voice in this conversational
patter is an early step in the progression of human cancers. Silencing an
inter-cell signaling mechanism called the interferon pathway may be one way
newly developing cancers gain the upper hand. It may also explain the immune
dysfunctions seen in many cancer patients and why cancer immunotherapies are
often ineffective.

"Over half of cancer patients mount an immune response against their own
cancer," said hematologist Peter P. Lee, MD, associate professor of hematology.
"So, why does it so often fail? Our research indicates that cancers interfere
with a critically important immune signaling pathway. There`s a possibility that
correcting this defect may one day become part of a useful treatment for many
types of cancer." Lee is the senior author of the research, which will be
published in the advance online version of Proceedings of the National Academy
of Sciences on May 18.

Clues that the interferon pathway is important in fighting off cancers come from
mouse models in which the pathway has been artificially disrupted. These animals
develop spontaneous tumors at higher rates than normal animals with functional
interferon signaling-showing that the immune system quashes many cancers in
their infancy. Some viruses are also known to inhibit the interferon pathway.

"It`s a very dynamic interaction," said 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." In other words, physicians and patients see only the immune system`s
defeats. This adds an additional hurdle to overcome for new cancer treatments
called immunotherapies that are meant to work by stimulating the patient`s
immune system to attack tumor cells.

Lee and his colleagues had previously shown that the interferon signaling
pathway was compromised in melanoma patients. In the current study, the
researchers investigated whether patients with two other types of cancer-breast
and gastrointestinal-also showed the same defect. They isolated immune cells
called 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. They found that lymphocytes from breast
cancer patients, as well as melanoma and gastrointestinal cancer patients,
expressed significantly lower levels of interferon-responsive signaling
molecules than did lymphocytes from healthy patients.

"They have a clear defect in the interferon signaling pathway," said Lee. When
the researchers looked more closely at the lymphocytes from breast cancer
patients, they 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. Finally, the researchers
showed that the immune cells from the breast cancer patients responded less
efficiently to external activation signals.

"It`s now looking like the interferon pathway may harbor a general immune defect
in many types of cancers," said Lee. He and his colleagues are working 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.

"Whatever functional defect these immune cells have likely impacts the
effectiveness of both active immunotherapy, like cancer vaccines, and passive
immunotherapy, like cellular therapies," said Lee. "If these forces are still at
play in vivo, the patient`s immune response to these types of treatments will be
blunted."

Other Stanford researchers who contributed to the work include postdoctoral
scholars Rebecca Critchley-Thorne, PhD; Ning Yan, PhD; Andrea Miyahira, PhD;
research assistant Diana Simons; associate professor of surgery Frederick
Dirbas, MD; associate professor of surgery Denise Johnson, MD; associate
professor of dermatology Susan Swetter, MD; professor of medicine Robert
Carlson, MD; associate professor of medicine George Fisher, MD; assistant
professor of radiation oncology Albert Koong, MD; and professor of statistics
Susan Holmes, PhD. The research was funded by a Department of Defense Era of
Hope Scholar Award.

The Stanford University School of Medicine consistently ranks among the nation`s
top 10 medical schools, integrating research, medical education, patient care
and community service. For more news about the school, please visit
http://mednews.stanford.edu. The medical school is part of Stanford Medicine,
which includes Stanford Hospital & Clinics and Lucile Packard Children`s
Hospital. For information about all three, please visit
http://stanfordmedicine.org/about/news.html.

Stanford University Medical Center
Krista Conger, 650-725-5371 (Print Media)
kristac@stanford.edu
Margarita Gallardo, 650-723-7897 (Broadcast Media)
mjgallardo@stanford.edu

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