NCI probes tumors’ effects on immune cell regulation

BETHESDA,Md.—Scientists at the National Cancer Institute (NCI) recently reported thatthe function of a type of cell that helps modulate immune responses is impairedinside tumors in mice.

Theresearchers also identified several factors that may contribute to anaccumulation of these cells, called T regulatory cells, or Tregs, within andaround the tumor, which may be how they respond to their loss of functionality.

Thestudy, Cellular Immunology and ImmuneRegulation: Tumor-Induced Impairment of TCR SignalingResults 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 wassupported by the Intramural Research Program of the Center for Cancer Researchand the National Institutes of Health.

Previousstudies have shown that the suppressive actions of Tregs require other immunecells to first become activated through the T cell receptor (TCR), a surfacelanding site where these cells recognize and bind to begin an immune response.

"This study demonstrates, for the first time, that murineregulatory T (Treg) cells in the tumor microenvironment display both enhancedproliferation and reduced functionality," the researchers wrote.

Inlaboratory experiments, Sabzevari's team demonstrated that Tregs taken from thespleens of mice bearing tumors exhibited a less suppressive influence on therate of proliferation of immune cells than did Tregs from spleens of the samestrain of mice without tumors. In addition, they found that suppression ofoverall immune responses decreased about 2.4-fold in tumor-associated Tregswhen compared to normal Tregs in the spleen.

Toexplore possible mechanisms for a tumor's effects on Treg cell function, theresearchers implanted cancer cells under the skin of mice. Then they comparedgene expression patterns in Tregs collected from spleen tumors that formed inmice implanted with Treg cells to expression patterns of spleens ofimplant-free control mice.

Microarrayanalysis revealed differences in the gene expression of several types of genes,including those involved in immune responses, signal transduction, T cellactivation, and the TCR signaling pathway. Comparing individual genes, theyfound reduced expression of several molecules that are involved in TCRsignaling in the tumor-associated Tregs when compared to normal Treg cells.

Astumors grew larger in implanted mice, the number of Treg cells increased inboth the spleen and in the tumors, but in tumors, the percent of Treg cellsactively copying themselves was 23 to 43 percent of the population of Tregscompared to 11 to 16 percent in the spleen. Additionally, cell death in thetumor-associated Tregs was two percent compared to 11 percent forspleen-associated Tregs in the same animals, likely because of the increasedexpression of other molecules that interfere with factors that signal celldeath.

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 maintainthemselves inside and in the environment immediately surrounding tumors will beimportant for designing new immunotherapies.

"Our findings indicate that treatments, such aschemotherapy or radiation therapy, can directly affect Treg cells," she says."By decreasing the number of Treg cells at the site of tumors, treatments, suchas immunotherapies, may be more effective."