Cancer evades immune
system by disarming T cells
BY MITCH LESLIE
The immune system, the
body's watchdog, often seems to nap while cancer sprouts
and spreads, permitting the rogue cells to run wild.
Using a speedy new method for analyzing immune system
activity, a Stanford-led research team has discovered how
the cancer manages to evade the normally watchful immune
system.
Although the body does
make anti-cancer cells, these cells have been muzzled so
that they won't attack their targets. Stanford
researchers think the cancer cells themselves may be
causing this inactivity.
Whether the immune system
even responds to cancer has been unclear and somewhat
controversial, said Peter P. Lee, MD, a postdoctoral
fellow in hematology and immunology and lead author of a
paper on the study, which was published in the June issue
of Nature Medicine. "It has been assumed that
because cancer cells come from our own bodies, the immune
system doesn't recognize them," he said. "And
so it has been assumed that patients develop cancer
because the immune system doesn't recognize the cancer
cells as abnormal."
However, some cancers do
produce antigens, the proteins that act as red flags for
the immune system, and anti-cancer immune cells are
occasionally found in tumors. Lee and Mark M. Davis, PhD,
professor of immunology and a Howard Hughes Medical
Institute investigator, teamed with scientists from three
other universities to isolate these anti-cancer cells and
test their responsiveness.
The researchers used a new
technique that Davis invented known as tetramer
analysis to quickly identify, count, and isolate the
immune cells called T cells. They looked for a specific
type of T cell known as a killer T cell, which locates
and destroys abnormal and infected cells.
The first step was to
analyze blood samples from 11 patients with metastatic
melanoma, in which the cancer had spread from its origin
in the skin. In six of the patients, there were
significant numbers of killer T cells targeted against
the melanoma, and in one patient, some 2 percent of all
the killer T cells in the blood were aimed at the cancer.
These measurements showed
that the immune system was responding about as vigorously
to the cancer as it would to a viral infection, Davis
said. So why didn't the killer T cells rout the cancer?
The answer emerged when
the researchers examined the T cells more closely. Cells
from all of the patients showed abnormal responses. For
example, when T cells from one patient were placed in a
miniature arena with melanoma cells, the T cells refused
to attack. When stimulated with antigens, T cells
normally produce copious amounts of a protein called
CD69, a telltale sign that the immune system is reacting.
But the patient's T cells did not. "Normally, T
cells are very responsive," Davis said. "Even
small amounts of antigen get them going."
Only the T cells aimed at
cancer cells exhibited this inhibition. Other killer
T cells responded normally to viruses, which eliminates
the possible explanation that the patients had faulty im-
mune systems.
The research team plans to
delve further into what restrains the T cells in hopes of
finding a way to reverse the inhibition. Early evidence
suggests the cancer cells are to blame. "What we've
found is that the cancer cells don't just sit there and
wait to be destroyed," Lee said. "They fight
back. One thing they do is turn off the cells that are
trying to destroy them."
Davis and Lee's Stanford
colleagues on the study include Denise L. Johnson, MD,
assistant professor of surgery; Susan Swetter, MD,
assistant professor of dermatology; Lawrence Fong, MD, a
postdoctoral fellow in pathology and at the Stanford
Blood Center; and graduate students Peter Savage and Dirk
Brockstedt. University of Washington collaborators
include Cassian Yee, MD, acting instructor in immunology
and medical oncology; John Thompson, MD, associate
professor of medicine; and Philip D. Greenberg, MD,
professor of medicine and immunology. The research team
also included Mario Roederer, PhD, assistant professor of
stomatology at the University of California-San
Francisco; and Jeffrey S. Weber, MD, associate professor
of medicine at the University of Southern California.
The research was funded by
the Howard Hughes Medical Institute and the National
Institutes of Health. SR
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