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

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-gamma production of T(H)1 cells and enhanced the suppressive capacity of regulatory T cells. Moreover, we identified an active role for HIF-1 alpha 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. (C) 2017 The Author(s) Published by S Karger AG, Basel