T cell-mediated immunity is a major component of anti-tumor immunity. In order to be efficient, effector T cells must leave the circulation and enter into the tumor tissue. We have shown that regulatory T cells (Treg) from gastric cancer patients, but not from healthy volunteers, potently inhibit migration of conventional T cells through activated endothelium. In this study, we compared T cells from colon cancer patients and healthy donors to determine the mechanisms used by Treg from cancer patients to inhibit conventional T cell migration. Our results showed that circulating Treg from cancer patients expressed high levels of CD39, an ectoenzyme mediating hydrolysis of ATP to AMP, as a rate-determining first step in the generation of immunosuppressive adenosine. Tumor-associated Treg expressed even more CD39, and we therefore examined the importance of adenosine in Treg-mediated inhibition of T cell transendothelial migration in vitro. Exogenous adenosine significantly reduced migration of conventional T cells from healthy volunteers, and blocking of adenosine receptors or CD39 activity during transmigration restored the ability of conventional T cells from cancer patients to migrate. Adenosine did not directly affect T cells or endothelial cells, but reduced the ability of monocytes to activate the endothelium. Taken together, our results indicate that Treg-derived adenosine act on monocytes and contribute to reduced transendothelial migration of effector T cells into tumors. This effect of Treg is specific for cancer patients, and our results indicate that Treg may not only affect T cell effector functions but also their migration into tumors.
- Received February 20, 2015.
- Revision received November 23, 2015.
- Accepted December 6, 2015.
- Copyright © 2016, American Association for Cancer Research.