"Conventional thinking and previous studies suggest that the tumor environment is responsible for immune dysfunction in cancer-fighting T lymphocytes that congregate at the site of a tumor. The major unresolved question is the origin and mechanism responsible for immune dysfunction in tumor-infiltrating T cells. We found that damaged T cells arose from a particular cell lineage, within a tumor environment that lacks factors promoting their survival," said Keith L. Black, MD, director of Cedars-Sinai's Maxine Dunitz Neurosurgical Institute, where the mouse studies were conducted. "Furthermore, we were able to influence the cells in a way that decreased the number of dysfunctional cells, a finding that we hope may eventually lead to more effective vaccine therapies against established tumors."
In a localized immune response, T cells are mobilized to attack cells that the immune system recognizes as invaders. Because specific lymphocytes recognize and attack specific immune threats, they are called "antigen-specific." In cancer vaccine experiments, such as those ongoing at the Institute to improve treatment for brain tumors, researchers seek to improve the immune response by helping cancer-fighting cells identify tumor cells as potential targets.
T cell activation is considered a major defense mechanism in the prevention of tumor formation, and in rodent studies T cell responses have been able to eradicate recently established tumors. In both humans and animals, however, T cell mobilization appears to have little effect when directed against advanced tumors.
While many types of T lymphocytes exist, differentiated by their molecular makeup and the roles they play, CD4 and CD8 cells are considered the "normal population" responding to threatening antigens. But in these studies, most T cells present within the tumors were "double-negative," expressing neither CD4 nor CD8, but instead exhibiting abnormal characteristics.
"While most studies assign T cell defectiveness and death to the tumor environment, we now know more about the kinds of T cells that are susceptible and how they become defective. This allowed us to target novel properties to prevent or reverse the defects," said Christopher J. Wheeler, PhD, research scientist and the paper's senior author. "The T cell defects could be incurred independent of their reactivity to the tumor per se, and on a general level involved signals for survival."
T cells normally receive "survival" signals provided by signaling molecules or certain hormones. In the absence of these survival signals, the cells simply die by default.
"These signals are usually available in the body but they evidently are not available to T cells in tumors," said Dr. Wheeler. "We conducted an experiment to test this observation, adding back the molecules that can induce such signals, and we found a reduction in the abnormal T cells."
The recent research also provides new insight into another aspect of the relationship between tumors and defective T cells. Because those T cells responding to a tumor are believed to be specifically reactive to that tumor antigen, it has been assumed - perhaps incorrectly - that the T cell defects were in some way related to antigen-specificity and reactivity.
"We placed non-activated and non-tumor-specific T cells into tumors and found that they readily became defective. This runs counter to the predominant paradigm holding that defectiveness is related to antigen reactivity or specificity. At least experimentally, this is not the case. Of course, in a real tumor, most of the T cells that are present are going to be antigen-specific. Antigen-specificity allows T cells to infiltrate tumors, but this is not necessarily involved in their defectiveness," Dr. Wheeler said.
If the findings in this series of experiments are supported through additional studies and their implications in animals are consistent in humans, they may help researchers devise more effective approaches to immunotherapy. Theoretically, at least, the vaccine would "turn on" the immune system and focus it on the tumor while the promotion of survival signals into the tumor would "repair" defective T cells to help them stay alive to fight.
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.