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National Cancer Institute (NCI)

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Friday, April 18, 2008
12:01 a.m. EDT

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Mouse Studies Show Tumors Suppress Cells Responsible for Regulating the Immune System

New research has shown that the function of a type of cell that helps modulate immune responses is impaired inside tumors in mice. Researchers also identified several factors that may contribute to an accumulation of these cells, called T regulatory cells (Tregs), within and around the tumor, which may be how they respond to their loss of functionality. The study, by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, appeared online April 18, 2008, in The Journal of Immunology.

"These findings provide insight into the impact of a growing tumor on the immune system," said Helen Sabzevari, Ph.D., of NCI's Center for Cancer Research, an author of the study. "Understanding the tumor's effects on Tregs and how these cells maintain themselves inside tumors, and in the environment immediately surrounding tumors, will be important for designing new immunotherapies."

Tregs are a specialized subset of T cells that help manage the immune system by suppressing the response of immune cells once a foreign invader has been defeated. They also prevent autoimmune diseases by keeping the body from attacking its own cells and tissues or reacting to its own antigens, called self-antigens. Since tumor-associated antigens are primarily derived from self-antigens, Treg cells also play an important role in suppressing immune responses directed against tumors, yet Tregs are thought to somehow escape the immunosuppressive effects of the tumor microenvironment.

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 triggers the eventual suppressive activity of Tregs through a step-wise series of biochemical events called signaling pathways.

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 vs. expression patterns of spleens of implant-free control mice. Microarray analysis — which allows researchers to examine the activity of thousands of genes simultaneously — 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.

Further analysis indicated that Treg cells in tumors lose some of their functionality because they do not become effectively activated. "Our studies demonstrate that Treg cells from tumors are less capable of responding to activation through the TCR than are Treg cells from normal spleens, indicating that the tumor microenvironment inhibits functionality of Treg cells," said Sabzevari.

In some human cancers, the number of Tregs increases in the peripheral blood, and these cells accumulate at the site of tumors. Increases in Treg cell numbers also have been observed in the spleen of animal tumor models.

Similarly, in this new research, 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.

Despite their reduced functionality, the accumulation of larger numbers of Tregs in tumors may still allow the suppression of antitumor immune responses. Targeting Treg cells may be one way of improving cancer immunotherapy.

"Our findings indicate that treatments, such as chemotherapy or radiation therapy, can directly affect Treg cells," said Sabzevari. "By decreasing the number of Treg cells at the site of tumors, treatments, such as immunotherapies, may be more effective."

For more information on Sabzevari's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5674.

For more information about cancer, please visit the NCI website at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Lutsiak MEC, Tagaya Y, Adams AJ, Schlom J, and Sabzevari H. Tumor-Induced Impairment of TCR Signaling Results in Compromised Functionality of Tumor-Infiltrating Regulatory T Cells. The Journal of Immunology. May 1, 2008.

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