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Cell Physiol Biochem. 2017;41(4):1271-1284. doi: 10.1159/000464429. Epub 2017 Mar 8.

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

Author information

1
Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
2
Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
3
Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Abstract

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 TH1 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.

KEYWORDS:

Colitis-associated colon cancer; HIF-1a; Hypoxia; T cell function

PMID:
28278498
DOI:
10.1159/000464429
[Indexed for MEDLINE]
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