Science Editor

As far as the immune system is concerned, the right hand doesn't know what the left is doing. And in the June 24, 2008, online edition of the Journal of the National Cancer Institute, researchers showed how that fact might be exploited by a new type of cancer vaccine that aims to prevent metastases.

The scientists reported using guanylate cyclase C, or GCC, a protein that is expressed by mucosal surfaces and on colon cancer cells, but usually not encountered by the central immune system, as what senior author Scott Waldman termed "the first example of a family of cancer mucosa antigens."

The immune system, Waldman explained, is basically two separate systems: the central immune system - itself made up of innate and adaptive systems - is what most people think of the "the" immune system.

But at the body's interface with the outside world, a second immune system reigns: the mucosal immune system. That immune system has its own antibodies and even a distinct set of lymph nodes from the central immune system.

The reason for the separation, Waldman explained, is that the inside of the body is sterile, and any pathogen that manages to breach that sterility needs to be stringently dealt with. "The central immune system is always on red alert," Waldman told BioWorld Today. "That's not true for mucosal surfaces."

If the classical immune system is the body's Pentagon, the mucosal immune system needs better diplomatic skills. At the interface between the body and the outside world, strangers abound, and the majority of them are harmless or even beneficial - the colon, for example, is colonized by thousands species of bacteria, and if the immune system turns on them, it appears the result can range from obesity to Crohn's disease. (See BioWorld Today, May 29, 2008.)

The separation of the two immune systems means that when tumors that have arisen from mucosal surfaces metastasize into the central compartment, the central immune system should be able to mount an immune response to them. But because the two immune systems remain separate, Waldman and his colleagues hypothesized that such an immune response "would not cross back over and cause inflammatory bowel disease" or other autoimmune reactions.

To test those predictions, Waldman, along with first author Adam Snook and colleagues from Thomas Jefferson University in Philadelphia and Amgen Inc. engineered a mucosal antigen that is expressed on colon cancer cells into viral vectors, and immunized mice either before or after injecting them with colon cancer cells.

The central immune system did indeed mount a response to GCC. Compared to nonimmunized controls, mice immunized with GCC either before or after injection of colon cancer cells had fewer lung and liver metastases and an increased survival time. To the scientists' surprise, though, the response was limited to killer T cells. Neither helper T cells nor B cells from the central immune system appeared to recognize GCC as foreign.

That selective response, Waldman said, was "the last thing we expected," adding candidly that "we actually didn't know what to expect - but this wasn't it."

He said he believes that the tolerance is probably specific to helper T cells, and suggested that the partial tolerance might represent a balance between immune diversity and autoimmunity, but stressed that both ideas are conjecture at this point.

The author's prediction that targeting the mucosal immune system would not lead to autoimmunity also was borne out.

"There's no evidence, not even a hint, of inflammation in any tissue including the intestines, which have GCC on their normal cells," Waldman said.

Waldman and his team plan to search for other immunogenic proteins in the mucosal immune system. The approach might be useful for a variety of other cancers, including lung cancer, head and neck cancers and certain types of breast cancer. They also are investigating other antigens that could be useful for colon cancer, with the ultimate goal of developing a polyvalent vaccine.

Waldman said that "we do not see immunizing the entire population. Most people are not going to develop colon cancer, and [universal vaccination] would not be a good use of limited health care resources."

Instead, he said, such a vaccine would be useful for colon cancer patients in remission, where it could prevent recurrence, and to those who have an increased risk of developing colon cancer - because they have a known genetic predisposition, relatives with the disease, or a propensity to form polyps. Such a vaccine would not prevent primary tumors from forming, but it could prevent metastases, which ultimately are what kills most cancer patients.