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

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 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.

Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

“…C). In another study in which mouse colons with colitis‐associated colon cancer (CAC) were observed to be more profoundly hypoxic than the colons of healthy mice, CAC mouse colons displayed an increased frequency of CD4 + Foxp3 + T cells and increased suppressive activity of CD4 + Foxp3 + T cells relative to the colons of healthy control mice (Fig. A).…”

“…Similarly, in non‐small cell lung cancer (NSCLC) patients, CD4 + CD25 + Tregs counts in peripheral blood are positively correlated with pathogenic grade and clinical stage of NSCLC and with the expression of HIF‐1α in NSCLC tissues . Despite the link between hypoxia and HIF‐1α in the colon and increased number and inhibitory activity of Tregs, the possibility that this effect is attributable to DC‐associated HIF‐1α, but not T cell‐associated HIF‐1α, cannot be excluded.…”

Can Exercise-Induced Modulation of the Tumor Physiologic Microenvironment Improve Antitumor Immunity?

“…Further, T-cell motility is reduced in hypoxia (74). In murine models of colorectal carcinoma, hypoxia reduced differentiation of CD4 þ T cells by 20% to 40%, while enhancing the number and function of Tregs (75). Hypoxic effector T cells exhibit decreased IFNg and IL2 production (62).…”

Current status of hepatopulmonary syndrome in liver transplantation in Japan: a Japanese multicenter analysis

“…reported that severe hypoxia was accompanied by decreased differentiation of CD4+ effector T cells and increased numbers and enhanced suppressive activity of regulatory T cells. Moreover, T cell stimulation under hypoxic conditions inhibited the differentiation and proliferation of Th1 cells, as well as IFN‐γ production by Th1 cells, and enhanced the suppressive capacity of regulatory T cells . Based on these reports, we hypothesized that hypoxia may correlate to ACR in the following ways: (1) the low oxygen levels in the endothelial cells in the liver until the patients recovered from HPS may account for the correlation; or (2) although low oxygen saturation in patients with HPS before LT may enhance immunosuppression, drastic changes of the hypoxic condition after LT may change the T cell condition, possibly leading to immune stimulation.…”