June 23, 2000 A team led by scientists at the University of California, San Francisco has identified five proteins in mice that trigger the immune system to attack cancer. The research greatly increases the number of known targets for drugs or vaccines to boost the immune system's natural cancer-fighting ability, the scientists say.
The proteins present in cancer cells, but not normal healthy tissues, mark these cells for swift attack by the immune system's natural killer (NK) cells. Although the proteins were discovered in mice, the scientists have evidence of their counterparts in humans. Two related proteins were identified in humans last year.
The research on the five new proteins and the genes that code for them is being reported by scientists at UCSF and the DNAX Research Institute in Palo Alto. In mice as well as humans, NK cells aggressively attack cancer cells once they are tagged by these proteins. This can be demonstrated using tumor cell cultures, where a single NK cell will destroy a marked cancer cell within a few minutes; then move on to eliminate the next enemy cell, the researchers point out. Studies are under way to determine if NK cells are equally aggressive in mice bearing tumors tagged with the newly discovered proteins.
"The immune system's natural killer cells are swift to attack once cancer cells are tagged as foreign," says Lewis Lanier, PhD, senior author on the paper reporting the research. "But cancer cells are part of one's 'self,' and the immune system usually has difficulty recognizing them as invaders." Lanier is professor of microbiology and immunology at the UCSF Comprehensive Cancer Center, part of the UCSF Medical Center.
With five more proteins identified that alert NK cells to attack, researchers have a number of new targets for drugs to strengthen the immune system's ability to fight cancer, Lanier suggests.
These proteins on cancer cells naturally bind to receptors on the surface of the NK cells. The chemical linkage between the receptor on the NK cell and the protein on the tumor unleashes a sequence of chemical events that destroy the cancer cells.
The NK receptors, known as NKG2D, are in plentiful supply, expressed on all NK cells and in other immune soldiers such as CD8+ T cells. Altogether, NKG2D receptors are found on about half of all immune cells, Lanier says.
"One of the major goals in cancer research is finding how to enhance the immune system's ability to fight the disease, just as we have contained smallpox and polio with vaccines," Lanier says. "The ultimate goal of this research is to deliberately establish auto-immunity against cancer."
If the NK receptors launch attacks against cancer whenever they detect the key proteins, some of the more deadly cancers have probably evolved a way to silence the genes coding for these proteins, Lanier suggests.
"If so, then finding drugs to turn these genes back on may provide a useful therapy against cancer," he says.
The new study is published in the current issue of the journal Immunity. First author is Adelheid Cerwenka, PhD, a post-doctoral researcher in Lanier's lab at UCSF, who recently moved with him from their prior laboratory at the DNAX Research Institute.
The NKG2D receptor is found in NK cells of both mice and humans. The two human proteins identified so far which link up with the receptors to launch attacks are known as MICA and MICB. Neither has been found in mice. Researchers had been wondering why the mouse had the NKG2D receptor, but no MICA or MICB. With the five new proteins identified, they are now surprised how many proteins bind to the NKG2D receptor, Lanier says.
"It is common for receptors to have more than one protein that binds to it, he says. "But finding five -- or seven, if we count the two human proteins identified last year -- is very unusual. We now have more targets for potential drugs either to directly boost the protein's expression or turn their genes back on if the cancer silences them," Lanier says.
When they searched the gene database for the five genes, Lanier and his colleagues were surprised to find that the genes had already been identified as ones that are active in the normal mouse fetus, but silent in normal, healthy adults. However, Cerwenka and her co-workers have now shown that these genes are turned back on in cancer cells in adult mice. This is very similar to prior reports of other "oncofetal" antigens -- genes that are active in embryonic life and tumor cells, but not present in normal healthy adult tissues. This striking phenomenon is a puzzle to cancer biologists.
With the five mouse genes now identified, the researchers are now developing a mouse model, first to confirm the role of the proteins in flagging invading cancers, and then to test ways to immunize mice against cancer -- a giant step toward developing anti-cancer vaccines for humans.
Co-authors on the paper with Cerwenka and Lanier, and colleagues in the research, are Alexander B.H. Bakker, PhD, and Jun Wu, PhD, postdoctoral fellows in microbiology and immunology at UCSF, and Terri McClanahan, PhD, Janet Wagner, and Joseph H. Phillips PhD, all scientists at the DNAX Research Institute.
The Sandler Family Supporting Foundation (UCSF) and Schering Plough Corporation (DNAX) funded the research.
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