Deadly cancer turns off genes, evading the immune system
A contagious cancer decimating Tasmanian devils makes itself invisible to the animals’ immune systems, which might otherwise fight it off, a new study shows.
Devil facial tumor disease shuts down production of proteins that normally decorate the surface of cells, telling the body whether a cell is its own or not. As a result, the devil’s immune system doesn’t recognize cancer cells from another devil as a potentially worrisome invader, Hannah Siddle, a marsupial geneticist at the University of Cambridge and an international group of collaborators report online March 11 in the Proceedings of the National Academy of Sciences.
The finding could lead to a way to stop the deadly disease. “It’s really the first hope that there could be a vaccine or immune therapy,” says Elizabeth Murchison of the Wellcome Trust Sanger Institute and the University of Cambridge. Murchison, who was not involved in the new study, discovered in 2009 that the tumor originated in cells insulating a single devil’s nerve fibers. Since that initial case, which probably occurred in the late 1980s or early 1990s, the disease has spread across eastern and central parts of Tasmania, killing every devil it infects.
Tasmanian devils have such low levels of genetic diversity that many researchers thought the animals’ immune systems couldn’t distinguish their own cells from other devils’, and wouldn’t recognize a tumor cell as foreign. Yet the marsupials aren’t exactly identical, Siddle says. Other studies have demonstrated that the animals reject skin grafts from one another, suggesting that the tumor cells should get the boot, too. But the devils don’t appear to mount any serious defense against the cancer.
Siddle and her colleagues discovered that devil facial tumor cells turn off genes that the immune system uses to distinguish between cells from its own body and foreign cells. Without the proteins made by these major histocompatibility, or MHC, genes, the tumor cell can conceal its true identity as both a cancer cell and tissue from another animal.
In tests of devil tumor cells done in lab dishes, the researchers were able to turn MHC genes back on with a dose of either an antifungal drug called Trichostatin A or an immune chemical called interferon gamma. Trichostatin A is known to affect gene activity. Dogs infected with a contagious cancer called canine transmissible venereal tumor keep the nonfatal cancer in check partly by making interferon gamma.
If the drug or the immune chemical works the same way in the animals as it did in cells, it could rev up the devil’s immune system to fight off the tumor, says study coauthor Jim Kaufman, an immunogeneticist at the University of Cambridge.
Tumor cells that have had their MHC genes turned back on might serve as vaccines. (The tumor cells would be killed before scientists injected them into the devils.) But other researchers aren’t so sure such a vaccine will work. Many tumors, including the contagious tumor that infects dogs, turn down production of MHC proteins. Yet immune cells still find and at least attempt to kill the cancers, unlike in the devils.
The devil facial tumor must take additional steps such as secreting chemicals to tamp down immune responses, says Robin Weiss, a virologist at University College London. To fight the devils’ disease, researchers will need to discover any other evasion strategies the tumor uses.
Siddle and Kaufman are already on the trail of the tumor’s other strategies and are working with collaborators in Tasmania to test a vaccine using cells with rebooted MHC genes.
H. V. Siddle et al. Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer. Proceedings of the National Academy of Sciences Published online March 11, 2013. [Go to]
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