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Date: May 8, 2007 4:13 AM
Subject: [MM-research] Stanford researchers identify immune dysfunction in
melanoma patients
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Contact: Amy Adams
amyadams@...
650-723-3900
Stanford University Medical
Center<http://med-www.stanford.edu/MedCenter/MedSchool>
Stanford researchers identify immune dysfunction in melanoma patients

STANFORD, Calif. -- 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.
###

EMBARGOED FOR RELEASE UNTIL: Monday, May 7, 2007, at 5 p.m. Pacific time to
coincide with publication in the Public Library of Science-Medicine
BROADCAST MEDIA CONTACT: M.A. Malone at (650) 723-6912 (
mamalone@...)

The work was funded by the National Institutes of Health. Other Stanford
researchers who contributed to the work include postdoctoral scholars Ning
Yan, PhD, and Serban Nacu, PhD; and Susan Holmes, PhD, professor of
statistics.

Stanford University Medical Center integrates research, medical education
and patient care at its three institutions - Stanford University School of
Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital
at Stanford. For more information, please visit the Web site of the medical
center's Office of Communication & Public Affairs at
http://mednews.stanford.edu.




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