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

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


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.

MeSH terms

  • Animals
  • Cell Differentiation / immunology*
  • Cell Hypoxia / immunology
  • Colitis / immunology*
  • Colitis / pathology
  • Colonic Neoplasms / immunology*
  • Colonic Neoplasms / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology
  • Immune Tolerance
  • Immunologic Surveillance*
  • Interferon-gamma / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IFNG protein, mouse
  • Interferon-gamma