Treg‐cell depletion promotes chemokine production and accumulation of CXCR3<sup>+</sup> conventional T cells in intestinal tumors

Akéus, Paulina; Langenes, Veronica; Kristensen, Jonas M.; Mentzer, Astrid von; Sparwasser, Tim; Raghavan, Sukanya; Quiding‐Järbrink, Marianne

doi:10.1002/eji.201445058

Cited by 35 publications

(60 citation statements)

References 49 publications

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“…2D, we observed that the ability of CD4 + Foxp3 + Tregs to suppress the proliferation of responder CD4 + T cells was enhanced when these cells were isolated from CAC mice. This is well in line with recent studies demonstrating that Tregs isolated from human and mouse colonic tumour tissues strongly suppressed the proliferation of tumour-infiltrating CD8 + and CD4 + T cells [21, 22]. …”

Section: Resultssupporting

confidence: 77%

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

Westendorf

Skibbe

Adamczyk

et al. 2017

Cell Physiol Biochem

173

108

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Background/Aims: Hypoxia occurs in many pathological conditions, including inflammation and cancer. Within this context, hypoxia was shown to inhibit but also to promote T cell responses. Due to this controversial function, we aimed to explore whether an insufficient anti-tumour response during colitis-associated colon cancer could be ascribed to a hypoxic microenvironment. Methods: Colitis-associated colon cancer was induced in wildtype mice, and hypoxia as well as T cell immunity were analysed in the colonic tumour tissues. In addition, CD4⁺ effector T cells and regulatory T cells were cultured under normoxic and hypoxic conditions and examined regarding their phenotype and function. Results: We observed severe hypoxia in the colon of mice suffering from colitis-associated colon cancer that was accompanied by a reduced differentiation of CD4⁺ effector T cells and an enhanced number and suppressive activity of regulatory T cells. Complementary ex vivo and in vitro studies revealed that T cell stimulation under hypoxic conditions inhibited the differentiation, proliferation and IFN-γ production of T_H1 cells and enhanced the suppressive capacity of regulatory T cells. Moreover, we identified an active role for HIF-1α in the modulation of CD4⁺ T cell functions under hypoxic conditions. Conclusion: Our data indicate that oxygen availability can function as a local modulator of CD4⁺ T cell responses and thus influences tumour immune surveillance in inflammation-associated colon cancer.

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Section: Resultssupporting

confidence: 77%

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

Westendorf

Skibbe

Adamczyk

et al. 2017

Cell Physiol Biochem

173

108

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“…As controls, APC min/+ mice were identically treated. By day 3 and 10, at least 90% of Treg were depleted in blood, intestine and tumors of DT treated APC min/+ /DEREG [20]. Mice were killed and organs harvested on day 12.…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, we could demonstrate that Treg from cancer patients, but not healthy volunteers, inhibit transendothelial migration of effector T cells in vitro and that effector T cells accumulate in intestinal tumors in vivo after Treg depletion [20, 25]. In this study, our aim was to elucidate the mechanisms whereby Treg reduced the lymphocyte accumulation in tumors, with a focus on cell migration and chemokine signalling.…”

Section: Introductionmentioning

confidence: 98%

“…We recently showed that Treg depletion results in an increased accumulation of effector T cells in intestinal tumors. This observation was accompanied by an increased intra-tumoral expression of the chemokines CXCL9 and CXCL10 [20]. These chemokines are both ligands to the Th1 associated chemokine receptor CXCR3, which is mainly expressed on activated Th1 cells, cytotoxic T cells, NK cells and dendritic cells [21].…”

Section: Introductionmentioning

confidence: 99%

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

Akéus

Szeponik

Ahlmanner

et al. 2018

Cancer Immunol Immunother

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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.

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“…However, diphtheria-toxinmediated FoxP3-expressing cell depletion in the Apc Min/1 mouse has been reported to increase intestinal T lymphocyte infiltrates with a proinflammatory stroma as a consequence [26]. Nevertheless, the functional significance of the CD25…”

mentioning

confidence: 99%

An increased CD25-positive intestinal regulatory T lymphocyte population is dependent upon Cox-2 activity in the Apcmin/+ model

Faluyi

Fitch

2017

Clinical and Experimental Immunology

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Treg‐cell depletion promotes chemokine production and accumulation of CXCR3⁺ conventional T cells in intestinal tumors

Abstract: Additional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 35 publications

References 49 publications

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

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

An increased CD25-positive intestinal regulatory T lymphocyte population is dependent upon Cox-2 activity in the Apcmin/+ model

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Treg‐cell depletion promotes chemokine production and accumulation of CXCR3+ conventional T cells in intestinal tumors

Abstract: Additional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 35 publications

References 49 publications

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

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

An increased CD25-positive intestinal regulatory T lymphocyte population is dependent upon Cox-2 activity in the Apcmin/+ model

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Treg‐cell depletion promotes chemokine production and accumulation of CXCR3⁺ conventional T cells in intestinal tumors