Nov. 4, 1998 For a small percentage of the population, it is known that the body's immune system can successfully mount an attack against their tumors, often without the person even knowing that a tumor exists. But this victory comes at a price, for the body then turns against itself and attacks brain cells, resulting in a rare debilitating neurological disease called paraneoplastic cerebellar disorder (PCD).
A team of researchers from The Rockefeller University, studying PCD patients, have now shown for the first time that humans are able to develop naturally occurring immunity to cancer. The study, reported in the November issue of Nature Medicine, provides support for the recent efforts to treat cancer patients by activating their immune response in a manner that would lead to tumor immunity, a treatment called immunotherapy. An understanding of naturally occurring tumor immunity is important for the development of better strategies to treat cancer.
"We have found an expanded population of killer T cells that is the likely mediator of tumor immunity," says senior author Robert B. Darnell, M.D., Ph.D., associate professor and head of the Laboratory of Molecular Neuro-Oncology at Rockefeller. Darnell is also an associate physician and associate medical director of The Rockefeller University Hospital, where the studies were performed.
Tumor-specific killer T cells have not previously been shown to be present in humans in significant numbers, although their detection in the current study was anticipated from animal models of cancer.
"We were able to identify these cells because we studied patients with known tumor immunity," explains primary author Matthew Albert, Sc.B., a biomedical fellow at Rockefeller and the Cornell University Medical College.
PCD is associated with breast and ovarian cancers and affects an estimated one out of every 1000 women who have these cancers. PCD patients usually come to clinical attention with severe neurological dysfunction, unaware that they have a tumor. Patients suffer from severe ataxia, as if they were falling down drunk all the time, and they cannot coordinate any of the muscles in their bodies, which makes it difficult to walk, talk and eat. Because the autoimmune attack is directed against only one part of the brain, the cerebellum, these individuals are perfectly aware and retain their cognitive abilities.
Among patients with PCD, two-thirds exhibit neurologic symptoms before the diagnosis of cancer, and nearly 90 percent have limited cancer when diagnosed. In comparison, only 50 to 60 percent of breast cancer patients and 25 percent of ovarian cancer patients come to clinical attention with limited stage disease. Thus, PCD is an ideal model for the study of tumor immunity in humans.
The tumors in these patients are kept in check because the immune system targets a protein called cdr2, an antigen that is usually expressed only in the cerebellum. While scientists do not yet know why the tumor cells produce cdr2, the aberrant expression of this protein by the tumor allows the body's immune system to fight off the cancer.
The brain is one member of a family of tissues in the body known as immune-privileged sites, places where the immune system normally does not penetrate. As a result, the immune system perceives the cdr2 antigens produced by the tumors as foreign invaders, activating T cells to repel the incursion. Once activated, the T cells can cross the blood-brain barrier, the brain's security checkpoint, and start attacking neurons in the cerebellum because they recognize cdr2 made by Purkinje neurons, the cells responsible for coordinating fine motor control.
The Rockefeller researchers studied four PCD patients. One patient was in the acute phase of the disease, while the other three were admitted with chronic disease. These patients were seen 18 days and five, six and nine months, respectively, after the onset of cerebellar dysfunction. After being diagnosed with PCD, all four patients were found to have gynecologic cancers: one patient had breast cancer, the other three had ovarian cancer. The scientists found evidence of killer T cells that were specific to the cdr2 antigen in the peripheral blood of both the acute and chronic PCD patients.
The paper also describes experiments that led to a refined model for the establishment of tumor immunity. The scientists "fed" tumor cells containing cdr2 to dendritic cells, and demonstrated that it was possible to activate cdr2-specific T cells. Dendritic cells are cells in the immune system that are responsible for talking to T cells and helping to direct responses to fight infection and tumors. Found in most tissues of the body, dendritic cells are among the most efficient antigen-presenting cells in the body.
This works builds on a significant discovery from The Rockefeller University published earlier this year in the March 5 issue of the journal Nature.
The researchers suggest the following model for naturally occurring tumor immunity. Tumor cells undergo apoptosis (pronounced a-puh-TOE-sis), a type of cell suicide or programmed death, and are "eaten" by the dendritic cells. This event allows the apoptotic tumor cells to transfer the cdr2 antigen to the dendritic cells and in turn activate the tumor-specific T cells.
"This finding has led to very exciting theories regarding tumor biology as well as the possibility of employing the body's own mechanism for therapeutic purposes," says Darnell.
"We believe that tumor cells are popping up all the time and that along with other known mechanisms of control, the immune system plays a role in killing off tumors," Albert says. "Cancer is the exception and, to form, the tumor must learn how to evade the immune system."
According to Darnell as well as others in the field, "This knowledge can be applied to treating people with cancer. What we have learned by studying patients with PCD will hopefully help others with breast and ovarian cancer who do not have evidence of tumor immunity."
Darnell's and Albert's co-authors on the paper are Jennifer C. Darnell, Ph.D., Nina Bhardwaj, M.D., Ph.D., and Loise Francisco, B.S., at Rockefeller and Armin Bender, M.D., formerly at Rockefeller and now at a research institution in Germany.
The study was funded in part by the U.S. Department of Defense, the National Multiple Sclerosis Society and a Medical Scientist Training Program grant from the U.S. National Institutes of Health (NIH). Clinical work at the RU Hospital General Clinical Research Center was supported in part by a General Clinical Research Center Grant from the National Center for Research Resources at the NIH.
Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. Thirty-three faculty members are elected members of the U.S. National Academy of Sciences, including President Wiesel and President-elect Arnold Levine.
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