Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APCmin/+ mice

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.Electronic supplementary materialThe online version of this article (10.1007/s00262-018-2161-9) contains supplementary material, which is available to authorized users.

YYFZBJS ameliorates colorectal cancer progression in ApcMin/+ mice by remodeling gut microbiota and inhibiting regulatory T-cell generation

“…Accumulating data also indicated that the percentage of Treg cells is inversely related to increasing the risk for the progression of cancer [60,61]. For CRC patients, increased numbers of Treg cells had been found in peripheral blood, tumor-draining lymph node (DLN), and tumor microenvironment.…”

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

“…Tregs reduce endothelial CXCL10 production and inhibit T-cell migration into tumours, and CXCR3-mediated signalling is crucial for lymphocyte accumulation in intestinal tumours. Therefore, immunotherapy aimed at Tregs depletion may be effective by increasing not only effector T cell activity but also their accumulation in tumours [ 138 ]. Depletion of Tregs in enterotoxigenic Bacteroides fragilis (ETBF)-colonized mice enhanced colitis but diminished the tumorigenesis associated with the shifting of the mucosal cytokine profile from IL-17 to IFN-γ.…”

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance

“…CRC-associated vascular endothelial cells tend to overexpress CXCL9 and CXCL10, both ligands for the CXCR3 chemokine receptor located on Th1 cells, whose activation positively regulates the degree of inflammatory infiltration. The sources of the aforementioned ligands may also be other immunologically competent cells such as T lymphocytes, B cells and monocytes [220]. Differences in the level of expression of these chemokines, depending on Tregs, may be the cause of varying TIL levels in cancers.…”