New study finds how cells with damaged DNA alert the immune system

07/01/05

Berkeley -- Research led by biologists at the University of California, Berkeley, has found that damage to a cell's DNA sets off a chain reaction that leads to the increased expression of a marker recognized by the body's immune system.

The new findings, to be published July 3 in an advanced online issue of Nature, shed light on a long-standing question of how the natural killer (NK) cells - which are able to attack tumors - can differentiate cells that are cancerous from those that are healthy.

"Our study is the first to show that there are mechanisms in place for the immune system to identify cancer cells," said Stephan Gasser, UC Berkeley post-doctoral researcher in molecular and cell biology and lead author of the paper. "It reveals how natural killer cells distinguish something they're supposed to get rid of versus something they're supposed to keep."

The researchers explain that the immune system is designed to detect and attack foreign invaders, but cancer cells present a special challenge because they are still the bodies own cells, albeit ones in which the genes have gone awry.

"Many scientists question the importance of the immune system in stemming the development of cancer," said David H. Raulet, professor of immunology at UC Berkeley's Department of Molecular and Cell Biology and senior investigator of the study. "Our research adds to recent evidence that the immune system plays a significant role."

The researchers put cultures of ovarian epithelial cells and fibroblasts from mice through a battery of abuse, including heat shock, pH changes, oxygen deprivation and starvation. However, the only type of stress that set off the sequence of events associated with impairment of a cell's genetic material -- the DNA damage pathway -- was exposure to radiation and chemotherapy drugs.

They found that cells in which the DNA damage pathway was triggered were the ones that exhibited an increase in the expression of special proteins on the cell surface. These "ligands" on the membrane are specific to the NKG2D receptor on natural killer cells and are used to flag damaged cells for destruction. There are several types of NKG2D ligands, but the best known is called Rae1.

Prior studies have shown that the DNA damage pathway is activated in precancerous lesions, as well as many advanced tumors. In addition, many cancer cells express Rae1. It has been known that when genetic abnormalities occur, the cell cycle is halted so that the cell has time to fix the damage before the DNA is replicated. If the damage is too severe for the cell to repair on its own, it can trigger cell death, a process known as apoptosis.

"All of this is happening autonomously within the cell," said Raulet. "What's new about our study is that we found that cells with damaged DNA can also involve other cells in the fight, triggering a mechanism that signals other cells - specifically NK cells - to attack. It could be another ingenious trick that the body uses to ward off cancerous cells."

Interestingly, the NKG2D receptor is also found on the CD8+ T cell, a type of immune cell that acts as a sentry with a long-term memory of prior invaders. These cells stand ready to find and destroy cells infected by viruses before the virus can spread.

"We don't have direct information about the role of the DNA damage pathway in regulating immune responses to infectious diseases, but given what we have shown here, it is certainly plausible that it contributes to the expression of the NKG2D ligand," said Raulet. "It may also be that the Rae1 ligand helps trigger T cell responses that contribute to long term specific immunity. It's certainly an area of research that warrants more study."

Other co-authors of the paper are Sandra Orsulic, assistant professor at the Massachusetts General Hospital Center for Cancer Research, and Eric Brown, assistant professor at the University of Pennsylvania School of Medicine.

Source: Eurekalert & others

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