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

Artikel i vetenskaplig tidskrift
Författare Paulina Akeus
Louis Szeponik
Filip Ahlmanner
Patrik Sundström
Samuel Alsén
Bengt Gustavsson
T. Sparwasser
Sukanya Raghavan
Marianne Quiding-Järbrink
Publicerad i Cancer Immunology Immunotherapy
Volym 67
Nummer/häfte 7
Sidor 1067-1077
ISSN 0340-7004
Publiceringsår 2018
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för kirurgi
Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi
Sidor 1067-1077
Språk en
Länkar dx.doi.org/10.1007/s00262-018-2161-...
Ämnesord 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
Ämneskategorier Cancer och onkologi

Sammanfattning

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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