title: 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 rate-determining first step in the generation of immunosuppressive adenosine. Tumor-associated Tregs 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 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.
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, and MIVAC (The Centre for Mucosal Immunobiology and Vaccines), University of Gothenburg, Göteborg, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Sundström
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, and MIVAC (The Centre for Mucosal Immunobiology and Vaccines), University of Gothenburg, Göteborg, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Stenstad
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, and MIVAC (The Centre for Mucosal Immunobiology and Vaccines), University of Gothenburg, Göteborg, Sweden.
authors.forename: Veronica
authors.initials: V
authors.lastname: Langenes
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, and MIVAC (The Centre for Mucosal Immunobiology and Vaccines), University of Gothenburg, Göteborg, Sweden.
authors.forename: Filip
authors.initials: F
authors.lastname: Ahlmanner
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, and MIVAC (The Centre for Mucosal Immunobiology and Vaccines), University of Gothenburg, Göteborg, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Theander
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, and MIVAC (The Centre for Mucosal Immunobiology and Vaccines), University of Gothenburg, Göteborg, Sweden.
authors.forename: Tapuka Gordon
authors.initials: TG
authors.lastname: Ndah
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, and MIVAC (The Centre for Mucosal Immunobiology and Vaccines), University of Gothenburg, Göteborg, Sweden.
authors.forename: Kamilla
authors.initials: K
authors.lastname: Fredin
authors.affiliation: Department of Surgery, Sahlgrenska University Hospital/Ostra, Göteborg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Börjesson
authors.affiliation: Department of Surgery, Sahlgrenska University Hospital/Ostra, Göteborg, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Gustavsson
authors.affiliation: Orega Biotech, Ecully, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Bastid
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, and MIVAC (The Centre for Mucosal Immunobiology and Vaccines), University of Gothenburg, Göteborg, Sweden. marianne.quiding-jarbrink@microbio.gu.se.
authors.forename: Marianne
authors.initials: M
authors.lastname: Quiding-Järbrink
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D000241:Adenosine / Q000502:physiology*; D015703:Antigens, CD / Q000378:metabolism; D001081:Apyrase / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D057705:Transendothelial and Transepithelial Migration
chemical_list: D015703:Antigens, CD; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine