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 APCmin/+ mouse model. By breeding APCmin/+ 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.
Highlights
Colorectal cancer (CRC) is the third most prevalent cancer form world-wide with approximately one million new cases diagnosed each year [1]
We have shown an accumulation of Tumor-infiltrating lymphocytes (TIL) after Treg depletion in APCmin/+ mice [20], it was not clear to what extent this resulted from increased migration into the tumor tissue
No significant differences in lymphocyte migration into mesenteric lymph nodes (MLN), spleen and unaffected small intestine were observed in Treg depleted A PCmin/+/ depletion of regulatory T cell (DEREG) mice compared to control mice (Fig. 1a)
Summary
Colorectal cancer (CRC) is the third most prevalent cancer form world-wide with approximately one million new cases diagnosed each year [1]. Tumor-infiltrating lymphocytes (TIL), like natural killer (NK) cells, CD8+ cytotoxic T cells and CD4+ T helper (Th) cells have all been found to promote antitumor immunity [2, 6]. Previous studies from both our group and others have demonstrated an accumulation of regulatory T cells (Treg) in both human [7,8,9] and mouse [10, 11] intestinal tumors. The full extent of Treg mediated immune suppression and its contribution to colon cancer progression is still not established
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
