Photo by Dean Forbes
You may not realize it, but there is a battle going on inside your body every day. Not only is your immune system in constant combat with invaders from the world at large, opposition may also come from within. Mutated cells, the domestic terrorists of the body, must be held in check by cells of the immune system. If these rogue cells can get past the body's defenses, the result is cancer.
For the past few years, Dr. Thomas Spies' laboratory in the Clinical Research Division has been studying ways in which mutated cells gain the upper hand. In the May 24 issue of Nature, Spies and colleagues reported a breakthrough in understanding one of the mechanisms tumor cells use to evade immune-system detection.
The scientists identified a protein that is required for tumor cells to rid themselves of distress-signals that notify the immune system that the cells are abnormal. This process of shedding the distress signals is known to be a key method tumor cells use to avoid immune system detection and ultimately, destruction. Understanding how this shedding process works could lead to treatments aimed at preventing shedding, making tumor cells more susceptible to immune system attack.
The MIC distress signal
Before joining the Hutchinson Center in 1994, Spies and co-workers discovered a class of unique distress signal proteins called MIC. These proteins are expressed on the surface of epithelial cells under conditions of stress, including cancer. MIC proteins are distant relatives of the classical major histocompatibility complex class-I proteins found on the surface of most cells that serve to alert T-cells when a cell is abnormal. The MIC proteins are unique in that they are nonspecific distress signals: their mere presence on the cell surface activates cells of the innate immune system called natural killer (NK) cells to kill any cell displaying the MIC distress signal. MIC also binds to T-cells, lowering the threshold for T-cell activation.
The fact that the body has such a system to detect and destroy cancerous cells is small consolation to the millions affected by cancer each year. Tumors evade immune system surveillance quite frequently and one of the main ways this evasion occurs is through MIC shedding. NK cells and T-cells normally recognize the MIC protein distress signal using a cell-surface receptor called NKG2D. When these lymphocytes recognize MIC on the surface of a tumor cell, they are activated to kill the offending cell. So, when tumor cells shed the MIC protein from their surface they are removing the tag that labels them for destruction. In addition, MIC proteins that are shed can bind to NK cells and T-cells and signal them to remove NKG2D from their surface, effectively making them deaf to the distress signals of all tumor cells.
The study began when Spies Lab scientist Dr. Veronika Groh discovered that one of the two types of MIC (called MICA) binds to an unknown protein on the surface of epithelial tumor cells. Next, Dr. Daesong Yim in Spies' lab purified the unknown protein and identified it as ERp5, which normally helps other proteins fold into the right shape inside cells. "The fact that tumor cells expressed surface ERp5, as well as MICA, suggested that it may have something to do with shedding," Spies said. Subsequent experiments by Groh and Dr. Segundo Gonzalez showed that inhibiting ERp5 in several cancer cell lines, either by adding drugs that block its action or by reducing its amount through genetic manipulation greatly reduced the amount of MIC that was shed. This showed that indeed, this protein was crucial to shedding the MIC-distress signal.
Spies next wanted to determine what ERp5 might be doing to cause shedding. Dr. I-Ting Chow in Spies' lab showed that ERp5 and MICA interact directly, resulting in shedding of MICA. Spies then sought help from a longtime collaborator and protein-structure expert, Dr. Roland Strong from the Basic Sciences Division. "He suggested independently studying these protein interactions in vitro," Spies said.
Dr. Brett Kaiser, a postdoctoral fellow in Strong's lab, examined how ERp5 affects MICA. "We were able to purify the proteins and analyze the biochemical activity of Erp5 in a test tube," Kaiser said. The results showed that in the presence of ERp5, a portion of the MICA protein becomes unraveled. "ERp5 is clearly having an effect on the protein," Strong said. "But, we don't know what it's doing that allows shedding to occur. That's what we want to figure out next."
Strong suggests that ERp5 might turn a portion of the MICA protein inside out. This large change in the shape of MIC may expose a portion of the protein that is normally protected deep inside it to ubiquitous protein-cutting enzymes called proteases. However, the protease (or proteases) responsible for cutting MICA and causing it to be shed remains unknown.
Having identified ERp5 as critical to the shedding process, a possible therapeutic avenue might be disrupting the interaction between ERp5 and MICA. "One approach may be, for instance, an antibody that would shield MICA from associating with ERp5," Spies said. If blocking this interaction keeps MICA from unraveling, shedding would be prevented allowing NK cells to remain vigilant in destroying tumor cells.
Even if therapies aimed at preventing shedding are successfully developed, they are unlikely to be a magic bullet against cancer. One limitation is that MIC proteins are only expressed on epithelial-cell tumors. Another issue is that shedding is just one of several methods of evasion used by cancer cells. In the constant battle that occurs between immune cells and tumor cells, every method the immune system has for detecting and destroying cancerous cells can be evaded by at least some tumor cells. But the work of Spies, Strong and colleagues adds to the arsenal of knowledge for use against the persistent threat of immune evasion.