Study published in The Journal of Immunology shows Tregs accumulate in large numbers, overcoming the fact that they are not effectively activated inside tumors.
A type of cell that helps modulate immune responses is impaired inside tumors in mice, according to the NCI. The 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.
Treg cells keep the body from attacking its own cells and tissues or reacting to self-antigens. Since tumor-associated antigens are primarily derived from self-antigens, Treg cells also play a role in suppressing immune responses directed against tumors. Yet, Tregs are thought to somehow escape the immunosuppressive effects of the tumor microenvironment, the investigators note.
The NIH team demonstrated that Tregs taken from the spleens of mice with tumors had a less suppressive influence on immune-cell proliferation than Tregs from spleens of mice without tumors. In addition, they found that overall immune-response suppression decreased about 2.4-fold in tumor-associated Tregs when compared to normal Tregs in the spleen.
The researchers then implanted cancer cells under the skin of mice. They compared gene-expression patterns in Tregs collected from the resulting spleen tumors with expression patterns of spleens of implant-free control mice.
They found differences in several types of genes including those involved in immune responses, signal transduction, T-cell activation, and the T-cell receptor (TCR) signaling pathway, which triggers the suppressive actions of Tregs. 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,” explains Helen Sabzevari, Ph.D., Center for Cancer Research and an author of the study.
Additionally, the researchers found that as tumors grew larger in mice, the number of Treg cells increased in both the spleen and in the tumors, which is similar to what happens in human cancers. Additionally, in tumors the percent of Treg cells actively copying themselves was 23 to 43% of the population of Tregs compared to 11 to 16% in the spleen. Also, cell death in the tumor-associated Tregs was 2% compared to 11% for spleen-associated Tregs.
Despite their reduced functionality, the accumulation of larger numbers of Tregs in tumors may still allow the suppression of antitumor immune responses, the scientists say. “Our findings indicate that treatments such as chemotherapy or radiation therapy can directly affect Treg cells,” says Dr. Sabzevari. “By decreasing the number of Treg cells at the site of tumors, treatments such as immunotherapies may be more effective.”
The study appears online on April 18 in The Journal of Immunology.
