Results of the study appear in the June issue of the European Journal of Immunology, and the research was conducted at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute, where clinical trials of dendritic cell immunotherapy have been underway for several years.
Dendritic cells are the immune system's most potent antigen-presenting cells - those that identify "foreign" substances for destruction. Because cancer cells often are not recognized by dendritic cells as antigens, the neurosurgeons and other scientists at the Institute have developed and studied a vaccine in the treatment of highly aggressive brain tumors called gliomas. They combine in the laboratory tumor cells that have been surgically removed and dendritic cells derived from a patient's blood. The new cells are injected back into the patient to seek out other cancer cells for destruction.
Early clinical trials have shown an increase in survival rates among patients receiving the dendritic cell vaccine. Meanwhile, Institute researchers have been studying underlying genetic and cellular mechanisms as well as other methods for increasing immune response and enhancing the vaccine's effectiveness.
"This study demonstrates that by turning off the interleukin 10 gene in the dendritic cell we can make a much more effective dendritic cell in terms of generating a significant immune response," said John S. Yu, MD, the article's senior author and co-director of the Comprehensive Brain Tumor Program at Cedars-Sinai.
One of the functions of dendritic cells is to influence immature T cells to become either T helper type 1 (Th1) or T helper type 2 (Th2) cells. A naturally occurring protein, interleukin 12 (IL-12), interacting with dendritic cells, spurs the development of Th1 cells. Interleukin 10 (IL-10) inhibits the production of IL-12.
"Interleukin 10 is a molecule that generates a Th2 response, which is effective against organisms such as bacteria, but for a tumor treatment a Th1 response is our goal. The Th1 response is generated through T cells against a tumor," said Dr. Yu.
In this study, the researchers used a new approach called RNA interference to target the IL-10 gene, inserting short strands of synthetic IL-10 specific RNA (small interfering RNA or siRNA) into dendritic cells generated from peripheral blood cells. Suppression of the IL-10 gene inhibited the secretion of the IL-10 protein, which allowed increased production of IL-12. Naïve T cells co-cultured with siRNA-treated dendritic cells developed into Th1 cells and generated a strong immune response in lab studies.
Keith Black, MD, director of the Maxine Dunitz Neurosurgical Institute, the Division of Neurosurgery and the Comprehensive Brain Tumor Program, said this is one of several ongoing studies aimed at making the dendritic cell vaccine more effective against the deadliest tumors.
"We are accumulating evidence that brain tumors themselves play a role in suppressing the T cell response, and we think this is one reason gliomas grow so quickly. The strategy of shutting down the IL-10 gene may be one way of counteracting this immune inhibition," said Dr. Black, who holds the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai.
The study was supported in part by National Institutes of Health grant number NS02232 to Dr. Yu.
Cedars-Sinai is one of the largest nonprofit academic medical centers in the Western United States. For the fifth straight two-year period, it has been named Southern California's gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthroughs in biomedical research and superlative medical education. It ranks among the top 10 non-university hospitals in the nation for its research activities.
Citation: European Journal of Immunology, June 2004: "Small interference RNA modulation of interleukin 10 in human monocyte-derived dendritic cells enhances the Th1 response."