A protein converts immune cells to tumor killers

Tumor cells are masters at evading detection. But new research from Rockefeller University shows how they can be exposed. By harnessing the immune system of patients with a rare neurological disorder, scientists have figured out how to transform immune cells that barely detect the presence of breast and ovarian tumors into ones that obliterate them.

The findings, which appear in this week’s issue of the Proceedings of the National Academy of Sciences, not only bring researchers closer to a therapy for gynecological cancers, but also to the key that could unlock the general secrets of tumor immunity.

“It’s a very romantic notion that the immune system recognizes tumors as foreign substances and kills them off,” says first author Bianca Santomasso, a biomedical fellow. “Instead of using the slash, burn and poison approach of surgery, radiation therapy and chemotherapy, we are trying to harness naturally occurring tumor immunity from patients with paraneoplastic cerebellar degeneration to treat ovarian and breast cancer patients.”

The research, led by Robert Darnell, a Howard Hughes Medical Institute investigator, head of Rockefeller's Laboratory of Molecular Neuro-oncology and Robert and Harriet Heilbrunn Professor in cancer biology, extends a hypothesis put forward by American and Australian scientists in 1957: Everybody develops tumors, but the immune system naturally kills off these cancerous cells day in and day out. The problem with this hypothesis, though, was that there wasn’t any way to test it since patients didn’t show any symptoms, explains Darnell, who is also a senior attending physician at The Rockefeller University Hospital.

The rare neurodegenerative disease called paraneoplastic cerebellar degeneration (PCD) provided researchers with the opportunity to test this hypothesis. It is thought that patients get this disease when the immune system recognizes and attacks a protein that is expressed in tumor cells; these immune cells kill the tumor and protect the body from cancer, but then they go one step too far: They infiltrate the brain and kill a group of neurons that also express this protein, an antigen called cdr2. When these patients go to the doctor to check out their neurological symptoms, they are told that they also have gynecological tumors — often small ones that have not metastasized.

“These PCD patients had tumors for a while, but they never knew,” says Darnell. “It is as if they developed an immune response to their own cancer.”

Unlike most patients with ovarian and breast cancer, patients with PCD have immune cells circulating in their blood that specifically target the cdr2 protein as well as the molecular platform on which it docks. Although this protein resides within tumor cells (not on their surfaces), these immune cells, called CD8+ cytotoxic T cells, can still “see” cdr2 because a section of this protein docks onto a molecular platform that ships it to the cell’s surface. Darnell and Santomasso’s work, with help from a number of laboratory colleagues, was the first to identify which section, or peptide fragment, was naturally attached to this molecular platform — an important finding because this interaction determines how cytotoxic T cells target the cdr2-expressing cells. When the T cell’s receptor binds to cdr2 and its platform, the immune cell releases substances that destroy the tumor.

In order to help breast and ovarian cancer patients, however, Santomasso and her colleagues needed to make the cancer patients’ immune cells like those of PCD patients — cells that could kill tumors that harbor the cdr2 protein. First, they injected healthy mice with the cdr2 protein and determined that the peptide fragment that bound most strongly to the platform was also the one most strongly recognized by CD8+ cytotoxic T cells. From these potent cdr2-specific CD8+ cytotoxic T cells, they isolated the genes that code for the T cell receptor. When the team injected the T cell receptor genes to normal human immune cells, the cells were able to target cdr2-expressing human tumor cell lines and kill them.

“I was astonished,” says Santomasso. “Human T cells can be transformed to specifically recognize antigens that are expressed in tumors and kill them. For breast and ovarian cancer patients, these findings hold great therapeutic promise.”

Source: Rockefeller University

Related stories:

You can be replaced: Immune cells compensate for defective DNA repair factor
A new mouse model has provided some surprising insight into XLF, a molecule that helps to repair lethal DNA damage. The research, published by Cell Press in the September 5th issue of the journal Molecular Cell, suggests that although XLF shares many properties with well known DNA repair factors, certain cells of the immune system possess an unexpected compensatory mechanism that that can take over for nonfunctional XLF.
Battling diabetes with beta cells
Affecting eight percent of America's population, diabetes can lead to blindness, kidney failure, strokes and heart disease. Thanks to Tel Aviv University researchers, a new cure –– based on advances in cell therapy –– may be within reach.
Early onset gene for inflammatory bowel diseases identified
A study of Crohn's disease and ulcerative colitis in children has identified a gene that influences whether children get these diseases early in life, and points to a potential new target for treatment. The findings of the international team that performed the study were published online this week by the journal Nature Genetics.
Study points to 1 cause of higher rates of transplanted kidney rejection in blacks
A Johns Hopkins research team reports it may have an explanation for at least some of the higher organ rejection rates seen among black - as compared to white - kidney transplant recipients. In a study of 50 healthy adult men, 25 black and 25 white, significantly different amounts of certain immune system cells were found between the races.
First gene associated with dry macular degeneration found
In a study that underscores the important role that individual genetic profiles will play in the development of new therapies for disease, a multi-institutional research team – led by Kang Zhang, MD, PhD professor of ophthalmology and human genetics at Shiley Eye Center at the University of California, San Diego, School of Medicine – has made two important discoveries related to age-related macular degeneration (AMD), the leading cause of blindness in adults over the age of 60.
Potential diabetes treatment selectively kills autoimmune cells from human patients
In experiments using blood cells from human patients with diabetes and other autoimmune disorders, Massachusetts General Hospital (MGH) researchers have confirmed the mechanism behind a potential new therapy for type 1 diabetes. A team led by Denise Faustman, MD, PhD, director of the MGH Immunobiology Laboratory, showed that blocking a metabolic pathway regulating the immune system specifically eliminated immune cells that react against a patient's own tissues.
Drug/radiation combo may help shrink established tumors
Researchers may be closer to understanding why anti-cancer drugs such as Ipilimumab, which boost the tumor-killing power of immune cells, haven't fared well in clinical trials. The new study, which describes a way to enhance the ability of these drugs to shrink well-established tumors, will be published online on August 25th in the Journal of Experimental Medicine.
New study shows health benefits of probiotic could extend to the entire body
Data from a recent study demonstrate the anti-inflammatory and pathogen protection benefits of Bifidobacterium infantis 35624 a probiotic bacterial strain of human origin. Gastrointestinal benefits of probiotics have been well-documented, but more and more research is revealing that probiotic benefits extend to the entire body. The report was published in the August issue of the Public Library of Science (PLoS) Pathogens.

News discussion:

Medicine & Health news