Regulatory T Cells from Colon Cancer Patients Inhibit Effector T-cell Migration through an Adenosine-Dependent Mechanism

Abstract

T cell-mediated immunity is a major component of antitumor immunity. In order to be efficient, effector T cells must leave the circulation and enter into the tumor tissue. 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 Tregs from cancer patients to inhibit conventional T-cell migration. Our results showed that circulating Tregs from cancer patients expressed high levels of CD39, an ectoenzyme mediating hydrolysis of ATP to AMP, as a ratedetermining first step in the generation of immunosuppressive adenosine. Tumor-associated Tregs expressed even more CD39, and we therefore examined the importance of adenosine in Tregmediated inhibition of T-cell transendothelial migration in vitro. Exogenous adenosine significantly reduced migration of conventional T cells from healthy volunteers, and blocking either adenosine receptors or CD39 enzymatic 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 acts on monocytes and contributes to reduced transendothelial migration of effector T cells into tumors. This effect of Tregs is specific for cancer patients, and our results indicate that Tregs may affect not only T-cell effector functions but also their migration into tumors.

Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APCmin/+ mice

“…In addition, human Treg also inhibit T cell transendothelial migration [12]. However, in mice there is only one isoform of CXCR3, while three different isoforms have been identified in humans (20).…”

The Escape of Cancer from T Cell-Mediated Immune Surveillance: HLA Class I Loss and Tumor Tissue Architecture

“…CD39 is an ectoenzyme, which serves as an integral component of the suppressive machinery of Tregs, inactivating and converting extracellular ATP into adenosine and allowing the immune escape of tumors. However, the high level of CD39 expression in both, CD4+ and CD8+ T cells, causes inhibition of the adhesion molecule expression necessary for transendothelial migration into the tumor and may explain the lack of infiltrating T-CD8 cells in the tumor nests [33]. …”

Immune Response in H. pylori-Associated Gastritis and Gastric Cancer

“…However, when Tregs were added back to the removed Treg fraction, a significant decrease in CD4+ T cell migration was observed. In addition, one year after the operation, transendothelial migration was restored in patients [44] (Figure 3).…”

“…Gastroenterology Research and Practice Interestingly, approximately 60% of the Tregs from cancer patients appear to have CD39+, while only about 30% of Tregs from healthy individuals express CD39+. The difference in CD39 expression suggests that CD39 is probably a crucial molecule to affect this disease [44]. A further research demonstrated that elevated CD39 and CD73 expression relates closely to poor prognosis in patients of gastric cancer and colorectal cancer [45].…”