Jan. 11, 1999 COLUMBUS, Ohio -- A newly discovered gene mutation that works like a master switch may enable tumor cells to evade destruction by the immune system, new research shows.
The finding presents extraordinary possibilities for both cancer treatment and for organ transplantation. Turning the gene back on in cancer cells might one day allow physicians to make tumors more recognizable to the immune system -- and therefore more subject to destruction by the body.
Turning off the gene in tissue to be transplanted, on the other hand, might make the tissue less recognizable to the immune system and therefore less likely to be rejected by the body.
"It is very important to establish how human cancer evades being eliminated by the immune system," said Yang Liu, Kurtz Chair Professor of Pathology at Ohio State University's Comprehensive Cancer Center.
"If we know how a tumor evades the immune system, we can study how to deal with it. This could lead to a way to increase the immune system's sensitivity to the tumor."
At the same time, said Pan Zheng, assistant professor of pathology and Liu's coworker, "in transplantation, we might use the switch to decrease the sensitivity of immune recognition and make the transplant more successful."
The discovery, published in the November 26 issue of the journal Nature, was made in tumors implanted into mice.
The study identified a master gene that controls the primary means by which cells alert the immune system of a problem -- that the cell is infected by a virus or that it has become cancerous, for example.
The system works by taking fragments of materials produced inside the cell and displaying those fragments on the outside of the cell. This work is done by major histocompatibility complex type I (MHC-I) molecules.
MHC-I molecules are produced deep inside the cell and are then transported to the cell surface. During that journey, a piece of a different molecule from elsewhere in the cell is attached to it. The MHC-I molecule carries that fragment to the cell surface where the fragment sticks out on display.
In this way, a bit of every protein produced in cells ends up displayed on the cell's surface.
These displayed fragments are routinely "inspected" by immune cells known either as killer T-cells or cytotoxic lymphocytes (CTLs). CTLs patrol the body and check the surface of cells for the molecular fragments displayed by MHC molecules.
If the fragments are those of proteins that are normal to the body, the CTL continues on its way. But if the fragment comes from a foreign protein -- such as a protein produced by a virus or an abnormal protein produced by a cancer cell -- the CTL destroys the cell.
In many types of cancer, however, the MHC-I system is shut down in tumor cells. Until this study, researchers didn't know why or how the MHC-I system was turned off.
"Our findings provide a very attractive explanation for that observation," said Liu.
Liu, Zheng, and their colleagues have found a mutation that shuts down the MHC-I transport system, a mutation which blocks the normal production of a protein known as PML.
Furthermore, the researchers found that PML activates four other genes, all of which are needed by the MHC-I system. Blocking just one of these genes would be enough to inactivate the MHC-I system, said Liu, but the loss of PML affects all four genes.
"That suggests it might be a master gene," said Liu.
The PML protein has been known for a while, he said, but its function was not clear. "To find PML linked to these genes was a surprise."
Zheng and Liu are now investigating the mechanism by which PML controls the four genes, and how that correlates with the progression of cancer in human tumors.
Zheng is also determining how frequently the PML gene goes awry in human tumors. MHC-I down-regulation is already known to occur in 80 percent of human prostate cancers, the researchers said. The PML malfunction may also contribute to the tumor's ability to spread to other areas of the body (i.e., to metastasize).
This research was supported by grants from the National Institutes of Health, Kaplan Comprehensive Cancer Center of New York University Medical Center, and by the Ohio State University Comprehensive Cancer Center.
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