Hutch News

Study by Groh, Spies yields clues to catching evasive tumor cells

Nov. 21, 2002

New experiments with tissue samples from patients with breast, lung and ovarian cancer have given Fred Hutchinson scientists important clues on how to catch tumor cells that evade the immune system, perhaps forestalling disease and death.

The study, led by Drs. Veronika Groh and Thomas Spies and colleagues in the Clinical Research Division, reveals how certain cancer cells can douse anti-tumor activity, permitting tumors to grow and spread unabated. The mechanisms involved are key to cancer's potentially lethal expansion and help explain how tumors manage to escape the body's disease-fighting machinery.

The findings appear in the Oct. 17 Nature.

At first glance, one such mechanism seems to have the opposite effect - it actually enhances the effectiveness of the immune attack launched to squelch cancer-promoting agents. But a study of health-defending warriors called T-cells from 39 cancer patients suggests there is more to this process than meets the eye.

Defense team

T-cells - so-called because they are processed in the thymus gland - comprise the immune system's component of white-blood cells called lymphocytes. The cells protect against viruses, bacteria, parasites and fungi. When any of the invaders are detected, the defense team is called to the rescue.

The T-cell contingent helps regulate the complex workings of the immune army or launches a direct assault. Among the attackers are natural killer cells, charged with decimating cancer and virus-infected cells. They act in the way their name implies, striking without first having to recognize specific antigens, or foreign invaders.

Another group, composed of cytotoxic T-cells, helps flush out cells that have been infected by viruses or tainted by cancer.

The tumors under study release copious amounts of specialized proteins called MIC, for major histocompatibility class I homologue, into the bloodstream, the researchers found.

The natural killers and lymphocytes press on with their attack when a receptor on their surface, called NKG2D, is activated. Receptors are proteins that serve as catcher's mitts for matching molecules, such as hormones, information-transmitting chemicals called neurotransmitters, antigens or antigen-disabling antibodies. Just as a key fits into a lock, so these molecules hook up with their intended partners to carry out their work.

Such a relationship exists between NKG2D and MIC. They cooperate to trigger the defense team's assault with intent to kill against infected cells, Spies' team discovered.

NKG2D resides on the surface of T cells and natural killer cells, helping them detect ailing cells, be they cancer-ridden or virus-infected, by seeking molecular clues. One of these is the cell surface protein MICA, one of two types of MIC molecules. A stressed cell synthesizes MICA, which spreads over the cell surface and acts as a distress signal. Recognition of MICA by NKG2D-bearing immune cells triggers a chain reaction that ends with the sick cell's demise.

The high levels of tumor-spawned MIC circulating in the blood appear to thwart the NKG2D receptor - in effect, stifling its anti-tumor effect.

Molecules abound

The usually scarce MIC molecules abound on epithelial tumors, which include breast, lung, colon, ovarian and prostate cancer and melanoma, Spies said.

"The function of this protein is to interact with a potent activating receptor, NKG2D, which is present on those T-cells of the body that have a capacity to fight tumor cells," he said. "In viral systems where these proteins are also induced, we have shown that, indeed, engagement by these proteins of the activating receptor potentially augments specific antiviral T-cell responses."

The same process was expected to occur in the war against tumors. But the studies showed low levels of the receptor, not only in T-cells residing in tumors, but also in those circulating in the blood of tumor patients, weakening their anti-cancer defense.

"This study shows that this loss of expression is due to the tumors shedding large amounts of the protein that interacts with the receptor in a soluble form," Spies said. "This shedding may present one of many mechanisms by which tumors evade immune-system control."

[Portions of this story are printed with the permission of United Press International.]

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