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

Journal article
Authors Paulina Akeus
Louis Szeponik
Filip Ahlmanner
Patrik Sundström
Samuel Alsén
Bengt Gustavsson
T. Sparwasser
Sukanya Raghavan
Marianne Quiding-Järbrink
Published in Cancer Immunology Immunotherapy
Volume 67
Issue 7
Pages 1067-1077
ISSN 0340-7004
Publication year 2018
Published at Institute of Clinical Sciences, Department of Surgery
Institute of Biomedicine, Department of Microbiology and Immunology
Pages 1067-1077
Language en
Links dx.doi.org/10.1007/s00262-018-2161-...
Keywords Regulatory T cells, CXCR3, APC(min/+), Colon cancer, Migration, colorectal-cancer, secreting cells, autoimmune-diseases, in-vivo, cxcr3, depletion, receptor, recruitment, t-helper-1, cd4(+), Oncology, Immunology
Subject categories Cancer and Oncology

Abstract

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.

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