Researchers from The Rockefeller University in New York City have developed a new method to fight cancer by using dendritic cells to activate T cells via a new pathway. Reported in the March 5 Nature, the technique offers the promise of new therapies for cancer, AIDS and autoimmune diseases.
"We've shown that dendritic cells can trigger an immune response when cultured with dying cells which carry an antigen, such as proteins from tumors or viruses," says lead author Matthew Albert, B.S., a biomedical fellow in the Laboratory of Cellular Physiology and Immunology at Rockefeller. "This is a new and very potent pathway for activating T cells."
Dendritic cells present antigens --proteins belonging to invaders, mutated pieces of the body's own tissue or normal self-tissue--to the body's T cells, directing responses to either fight or tolerate these molecules. (Tolerance is essential in order to prevent attack against one's own tissues.) Found in most tissues of the body, dendritic cells are among the most efficient antigen-presenting cells in the body.
The immune system recognizes antigens after going through a complex process of education, learning to distinguish self from non-self. Cancer results when the immune system fails to identify tumors as "foreign."
Current treatments for cancer, such as chemotherapy or radiation, target rapidly dividing tumor cells, but lead to serious side-effects because they attack healthy cells as well as tumors. Scientists are looking for more specific ways to attack tumor cells without damaging healthy cells.
One such technique is immunotherapy, which attempts to activate the immune system to recognize tumors as foreign and reject them, based on tumor-specific antigens that are presented on a molecule called MHC, a highly diverse set of proteins responsible for allowing dendritic cells to communicate with T cells. MHC molecules are different in each person, giving each individual a unique immune system. Even the most common MHC molecule is found in only 50 percent of Caucasians. This requires scientists to devise "designer" strategies, determining which antigens are specific to certain tumors and which parts of these proteins are presented on the patient's MHC, to effectively fight cancer.
The new work by Albert and his co-authors, Postdoctoral Associate Birthe Sauter, M.D., and Assistant Professor Nina Bhardwaj, M.D., Ph.D., provides an avenue for using the cell's natural machinery to bypass this requirement, allowing the individual's own dendritic cell to determine the correct part of the tumor antigen that fits their MHC molecules. In a model system, the researchers collected human tissue and infected it with influenza. These cells were triggered to undergo apoptosis (pronounced a-puh-TOE-sis), a type of cell suicide or programmed death. The dying cells were cultured with dendritic cells, making the dendritic cells capable of activating killer T cells that specifically target influenza antigen.
"In other words, the dendritic cells have the ability to acquire antigens from other cells and make them recognizable by T cells," says Bhardwaj, senior author of the paper. "The T cells, in particular the CD8+ killer cells, can then proceed to kill any other cell that contains tumor or viral antigens. It appears that only dendritic cells--and not cells like monocytes--have this ability."
One possible use for this technique is tumor immunotherapy, in which an individual's own tumors--or tumor cell lines containing antigens similar to the person's tumor--could be used a "apoptotic food," says Albert.
"The advantage of this technique is that we could use a person's immune system to choose the appropriate pieces of protein to be presented to the MHC, overcoming the need for designer immunotherapy," continues Albert. "In this way, an individual's own immune system is revved up to attack the tumor based on the expression of tumor-specific antigens."
The diversity of tumors and the fact that each person's immune system is unique complicates tumor immunotherapy. Scientists need to match specific protein fragments derived from a person's tumor to his or her MHC molecule.
"The discovery of this new pathway allows the dendritic cell's natural machinery to decide which pieces of the protein are useful to an individual's immune system," says Albert. "We hope that immunotherapy will be available for people with immune systems that don't match common MHC types."
On a historical note, the dendritic cell was discovered at Rockefeller in 1973 by Henry G. Kunkel Professor Ralph M. Steinman, M.D., and the late Zanvil A. Cohn, M.D.
Funding for this work was provided in part by the National Institute of Allergy and Infectious Diseases, part of the federal government's National Institutes of Health (NIH), and by the NIH Medical Scientist Training Program.
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. The university recently created six centers to foster collaborations among scientists to pursue investigations of Alzheimer's disease, of biochemistry and structural biology, of human genetics, of immunology and immune diseases, of sensory neurosciences and of the links between physics and biology.
Journal
Nature