6/7/99
MEDIA CONTACT: Mitchell Leslie (), (650) 725-5371 or (650) 723-6911
FOR COMMENT: Mark M. Davis, PhD, (650) 723-7962; Peter P. Lee, MD, (650) 723-7218
STANFORD - 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. Researchers from the Stanford University School of Medicine think that the cancer cells themselves may be causing this inactivity, shutting down their potential attackers.
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 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 or the lymph nodes. 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 out of 11 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 had not increased production of the protein. "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 immune systems.
Davis, Lee and colleagues plan 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."
Lee described a continuous battle between the cancer cells and the immune system in which each side tries to outmaneuver the other. "In patients who get cancer, the cancer is winning the battle."
The results also make designing cancer vaccines more complicated. Scientists have long dreamed of enlisting the immune system to fight cancer through vaccination, but the results so far have been mixed. What the new research shows, Davis said, is that while vaccines may stimulate T cells, "they aren't going to be as responsive to vaccination as virus-specific cells."
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 oncology; 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 grants from the Howard Hughes Medical Institute and the National Institutes of Health.
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