Intratumor Hypoxia Promotes Immune Tolerance by Inducing Regulatory T Cells via TGF-β1 in Gastric Cancer

Abstract

Regulatory T cell (Treg)-mediated immunosuppression represents one of the crucial tumor immune evasion mechanisms and is a main obstacle for successful tumor immunotherapy. Hypoxia, a common feature of solid tumors, has been associated with potentiated immunosuppression, decreased therapeutic response, malignant progression and local invasion. Unfortunately, the link between hypoxia and Treg-mediated immune tolerance in gastric cancer remains poorly understood. In our study, Tregs and hypoxia inducible factor-1α were found to be positively correlated with each other and were increased with the tumor progression. A subsequent in vitro study indicated that supernatants derived from gastric cancer cells under hypoxic condition, could induce the expression of Foxp3 via TGF-β1. These findings confirmed the crucial role of Tregs as a therapeutic target in gastric cancer therapy and provided helpful thoughts for the design of immunotherapy for gastric cancer in the future.

Intermittent Hypoxia-induced Changes in Tumor-associated Macrophages and Tumor Malignancy in a Mouse Model of Sleep Apnea

“…However, as shown herein, the interactions and specific functions assumed by the parallel alterations in Tregs and MDSCs in the context of IH will definitely have to be examined in greater detail in future studies, particularly considering how these host-derived immune cells operate in an exquisitely coordinated fashion within the tumor microenvironment (29). Indeed, the increased numbers of Tregs and MDSCs within the tumors of mice exposed to IH and their ability to suppress the immune system and to develop a protumor environment would justify such efforts (14,20,30).…”

Changes in the coelomic microclimate during carbon dioxide laparoscopy: morphological and functional implications

“…Treg-mediated immunosuppression allows immune evasion by tumour cells as they are able to overcome the activity of natural killer cells, dendritic cells and CD8 cytotoxic cells. Expression of HIF-1α and Treg cells were also positively correlated, but HIF-1α was not correlated with the induction of TGFβ under hypoxia [80].…”

Hypoxia-inducible factors: a central link between inflammation and cancer

“…Tumor hypoxia increases T cell expression of FoxP3 through tumor secretion of TGF-β in vitro, suggesting that hypoxic tumor cells can induce Treg differentiation (108). Tregs are more efficiently activated systemically than within the tumor microenvironment (109), and tumor secretion of cytokines such as TGF-β may be a critical source of systemic Treg activation and infiltration into tumors.…”