NCI probes tumors’ effects on immune cell regulation
BETHESDA, Md.—Scientists at the National Cancer Institute (NCI) recently reported that the function of a type of cell that helps modulate immune responses is impaired inside tumors in mice.
The researchers also identified several factors that may contribute to an accumulation of these cells, called T regulatory cells, or Tregs, within and around the tumor, which may be how they respond to their loss of functionality.
The study, Cellular Immunology and Immune Regulation: Tumor-Induced Impairment of TCR Signaling Results in Compromised Functionality of Tumor-Infiltrating Regulatory T Cells, was published online April 18 in The Journal of Immunology. In addition to the NCI, the research was supported by the Intramural Research Program of the Center for Cancer Research and the National Institutes of Health.
Previous studies have shown that the suppressive actions of Tregs require other immune cells to first become activated through the T cell receptor (TCR), a surface landing site where these cells recognize and bind to begin an immune response.
"This study demonstrates, for the first time, that murine regulatory T (Treg) cells in the tumor microenvironment display both enhanced proliferation and reduced functionality," the researchers wrote.
In laboratory experiments, Sabzevari's team demonstrated that Tregs taken from the spleens of mice bearing tumors exhibited a less suppressive influence on the rate of proliferation of immune cells than did Tregs from spleens of the same strain of mice without tumors. In addition, they found that suppression of overall immune responses decreased about 2.4-fold in tumor-associated Tregs when compared to normal Tregs in the spleen.
To explore possible mechanisms for a tumor's effects on Treg cell function, the researchers implanted cancer cells under the skin of mice. Then they compared gene expression patterns in Tregs collected from spleen tumors that formed in mice implanted with Treg cells to expression patterns of spleens of implant-free control mice.
Microarray analysis revealed differences in the gene expression of several types of genes, including those involved in immune responses, signal transduction, T cell activation, and the TCR signaling pathway. Comparing individual genes, they found reduced expression of several molecules that are involved in TCR signaling in the tumor-associated Tregs when compared to normal Treg cells.
As tumors grew larger in implanted mice, the number of Treg cells increased in both the spleen and in the tumors, but in tumors, the percent of Treg cells actively copying themselves was 23 to 43 percent of the population of Tregs compared to 11 to 16 percent in the spleen. Additionally, cell death in the tumor-associated Tregs was two percent compared to 11 percent for spleen-associated Tregs in the same animals, likely because of the increased expression of other molecules that interfere with factors that signal cell death.
Dr. Helen Sabzevari of NCI's Center for Cancer Research and an author of the study, says understanding the tumor's effects on Tregs and how these cells maintain themselves inside and in the environment immediately surrounding tumors will be important for designing new immunotherapies.
"Our findings indicate that treatments, such as chemotherapy or radiation therapy, can directly affect Treg cells," she says. "By decreasing the number of Treg cells at the site of tumors, treatments, such as immunotherapies, may be more effective."