Targeted treatments and immunotherapy are two of the most promising approaches to cancer, and each may one day be transformed by basic research on natural killer (NK) cells.

Stem cells in the bone marrow produce most of the immune system's components, including the white blood cells known as lymphocytes. Between 2 and 20 percent of these are NK cells, specialized lymphocytes that continuously patrol the body, eliminating cells that undergo malignant transformation.

Natural killers are aptly named because they act like commandos on a search-and-destroy mission for virally infected and cancerous cells. This streamlined, "ready-to-go" role for NK cells is part of the innate immune system "and makes them well suited for an early defense," explains Dr. Mary Carrington, director of NCI's Basic Science Directorate of NCI's Center for Cancer Research (CCR) in Frederick, Md.

An emerging view of carcinogenesis suggests there is often a long, silent, precancerous period where normal cells begin to undergo alterations, leading eventually to clinical disease. It would make sense if the immune system recognized these threats earlier, when they are easier to combat. "NK cells may have evolved, in part, for this very task," says Dr. Carrington.

How do they do it? Patrolling NK cells first lock onto potential target cells. Then a number of receptors search for complementary molecules on the target. Each receptor finding a match sends an internal signal, which varies not only in its basic message - destroy or ignore - but also in its strength. If the final message says "destroy," the NK makes holes in the target's membrane with the protein perforin, enabling enzymes to enter and destroy the cell's DNA.

Scientists such as Dr. Stephen Anderson, senior principal investigator at NCI-Frederick's Laboratory of Experimental Immunology in CCR, are trying to learn more about how a single cell can make such a complex sequence of calculations and judgments.

In mice, where most experimental work is done, the job of recognizing "self" falls to the Ly49 family of receptors. In humans, killer cell immunoglobulin-like receptors perform this function.

"We have identified a large number of Ly49 inhibitory receptor genes in mice, but a given NK cell does not express them all," explains Dr. Anderson. "The gene for each of these receptors has a unique DNA switch, which turns some 'on' and others 'off' in a random fashion. Thus individual NK cells become 'specialists,' trained to recognize only certain types of threats." The variety of receptors expressed across the population of patrolling NK cells will recognize a number of viruses, as well as signatures characteristic of cancer cells.

Though now a very promising area of immunology and cancer research, two decades ago NKs were under-appreciated, often referred to as "null" cells. But a few scientists, such as Dr. Klas Kärre of the Karolinska Institute in Stockholm, saw them as a black box that should be unlocked. The breakthrough idea emerged in 1986 and is now known as the "missing-self" model.

"In vertebrates, nearly all cells express glycoproteins known as HLA Class I, the genes for which are highly variable across the population," explains Dr. Carrington, whose lab has helped fill in the HLA picture. Yet they produce a signature common to all cells within each individual. In the clinical context, this pattern confers a person's tissue type, a crucial factor in whether a transplanted organ will be rejected. Insights from NK cell research may one day lead to more successful bone marrow transplants.

When NK cell inhibitory receptors that recognize "self" detect a person's own HLA on a cell, the basic message: "This one is us and healthy, let it be!" usually prevents the destruction of the cell. Not coincidentally, many cancer cells have downregulated these "self" proteins and are thus recognized as prime targets for destruction.

"The 'missing-self' hypothesis was brilliant and foresighted, but we have been able to refine it in several important ways," says Dr. Lewis Lanier, professor and vice chair of the Department of Microbiology and Immunology at the University of California, San Francisco.

"When NKs and potential target cells meet, we now see the inhibitory receptors acting more like a dimmer switch than an on-off switch. Information is interpreted by an analog, not a binary process," he explains. The cell essentially combines signals from a number of inhibitory and activating receptors to arrive at the final destroy-or-ignore decision.

Over time, NK cells have waged a kind of war with viruses in the body. NK cell receptors have evolved to recognize specific molecules that mark certain cancer signatures and viruses, such as human cytomegalovirus.

But viruses - and no doubt some cancers - also persist by evolving to outsmart the immune system of their potential host, and "some of the more deadly cancers have also evolved a way to silence the genes coding for the proteins recognized by NK cell activating receptors," suggests Dr. Lanier.

A few years ago, with NCI support, Dr. Lanier's lab identified molecules that are preferentially expressed on tumors for an important activating receptor known as NKG2D. Certain cancers may have evolved a way to turn off genes that encode for these molecules, and thus deceived the NK cell. "If we could develop ways to turn these genes back on, we would be much closer to a vaccine for cancer," says Dr. Lanier.

By Addison Greenwood