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Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice

Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased level...

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Autores principales: Akeus, Paulina, Szeponik, Louis, Ahlmanner, Filip, Sundström, Patrik, Alsén, Samuel, Gustavsson, Bengt, Sparwasser, Tim, Raghavan, Sukanya, Quiding-Järbrink, Marianne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006230/
https://www.ncbi.nlm.nih.gov/pubmed/29671006
http://dx.doi.org/10.1007/s00262-018-2161-9
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author Akeus, Paulina
Szeponik, Louis
Ahlmanner, Filip
Sundström, Patrik
Alsén, Samuel
Gustavsson, Bengt
Sparwasser, Tim
Raghavan, Sukanya
Quiding-Järbrink, Marianne
author_facet Akeus, Paulina
Szeponik, Louis
Ahlmanner, Filip
Sundström, Patrik
Alsén, Samuel
Gustavsson, Bengt
Sparwasser, Tim
Raghavan, Sukanya
Quiding-Järbrink, Marianne
author_sort Akeus, Paulina
collection PubMed
description Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors. In this study, we investigated the mechanisms for Treg mediated suppression of T-cell migration into intestinal tumors in the APC(min/+) mouse model. By breeding APC(min/+) mice with DEREG mice, which harbour a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, we were able to deplete Treg in tumor-bearing mice. Using adoptive transfer experiments, we could document a markedly increased migration of T cells specifically into Treg depleted tumors, and that Treg depletion results in increased production of the CXCR3 ligand CXCL10 from endothelial cells in the tumors. Furthermore, we were able to demonstrate that T cells use CXCR3 to migrate into intestinal tumors. In addition, human colon adenocarcinomas express high levels of mRNA CXCR3 ligands and tumor endothelial cells produce CXCL9 and CXCL10 ex vivo. In conclusion, this study demonstrates that Treg reduce endothelial CXCL10 production, inhibit T-cell migration into tumors and that CXCR3 mediated signalling is crucial for lymphocyte accumulation in intestinal tumors. Thus, immunotherapy aimed at Treg depletion may be effective by increasing not only T effector cell activity, but also their accumulation in tumors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-018-2161-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-60062302018-07-04 Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice Akeus, Paulina Szeponik, Louis Ahlmanner, Filip Sundström, Patrik Alsén, Samuel Gustavsson, Bengt Sparwasser, Tim Raghavan, Sukanya Quiding-Järbrink, Marianne Cancer Immunol Immunother Original Article Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors. In this study, we investigated the mechanisms for Treg mediated suppression of T-cell migration into intestinal tumors in the APC(min/+) mouse model. By breeding APC(min/+) mice with DEREG mice, which harbour a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, we were able to deplete Treg in tumor-bearing mice. Using adoptive transfer experiments, we could document a markedly increased migration of T cells specifically into Treg depleted tumors, and that Treg depletion results in increased production of the CXCR3 ligand CXCL10 from endothelial cells in the tumors. Furthermore, we were able to demonstrate that T cells use CXCR3 to migrate into intestinal tumors. In addition, human colon adenocarcinomas express high levels of mRNA CXCR3 ligands and tumor endothelial cells produce CXCL9 and CXCL10 ex vivo. In conclusion, this study demonstrates that Treg reduce endothelial CXCL10 production, inhibit T-cell migration into tumors and that CXCR3 mediated signalling is crucial for lymphocyte accumulation in intestinal tumors. Thus, immunotherapy aimed at Treg depletion may be effective by increasing not only T effector cell activity, but also their accumulation in tumors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-018-2161-9) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2018-04-18 2018 /pmc/articles/PMC6006230/ /pubmed/29671006 http://dx.doi.org/10.1007/s00262-018-2161-9 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Akeus, Paulina
Szeponik, Louis
Ahlmanner, Filip
Sundström, Patrik
Alsén, Samuel
Gustavsson, Bengt
Sparwasser, Tim
Raghavan, Sukanya
Quiding-Järbrink, Marianne
Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
title Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
title_full Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
title_fullStr Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
title_full_unstemmed Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
title_short Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
title_sort regulatory t cells control endothelial chemokine production and migration of t cells into intestinal tumors of apc(min/+) mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006230/
https://www.ncbi.nlm.nih.gov/pubmed/29671006
http://dx.doi.org/10.1007/s00262-018-2161-9
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