Hypoxia induces T-cell apoptosis by inhibiting chemokine C receptor 7 expression: the role of adenosine receptor A2

Abstract

Hypoxia is a major characteristic of the tumor microenvironment, and its effects on immune cells are proposed to be important factors for the process of tumor immune escape. It has been reported that hypoxia affects the function of dendritic cells and the antitumor function of T cells. Here we discuss the effects of hypoxia on T-cell survival. Our results showed that hypoxia induced apoptosis of T cells. Adenosine and adenosine receptors (AR) are important to the hypoxia-related signaling pathway. Using AR agonists and antagonists, we demonstrated that hypoxia-induced apoptosis of T cells was mediated by A 2a and A 2b receptors. Furthermore, we are the first, to our knowledge, to report that hypoxia significantly inhibited the expression of chemokine C receptor 7 (CCR7) of T cells via the A 2 R signal pathway, perhaps representing a mechanism of hypoxia-induced apoptosis of T cells. Collectively, our research demonstrated that hypoxia induces T-cell apoptosis by the A 2 R signaling pathway partly by suppressing CCR7. Blocking the A 2 R signaling pathway and/or activation of CCR7 can increase the anti-apoptosis function of T cells and may become a new strategy to improve antitumor potential.

Immunosuppressive Effects of Multipotent Mesenchymal Stromal Cells in Cultures with Different O2 Content in the Medium

“…Culturing at low pO 2 (5% O 2 ) did not change the percent of viable cells, which agrees with previous data [1]. Other investigators revealed increased viability of lymphocytes under condition of hypoxia [12,15] and induction of apoptosis in T lymphocytes under conditions of reduced O 2 content [16]. It is known that MMSC maintain viability of both non-activated [4] and activated lymphocytes [18].…”

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…Adenosine strongly impairs development of effector T cells, especially those that produce IFN-γ and are cytotoxic to tumor cells [84]. Sun et al reported that hypoxia can induce T-cell apoptosis through adenosine/adenosine (2) receptor signaling in vitro [85]. Cytotoxic activity by NK cells is also restrained by hypoxia.…”

Mechanisms of Hypoxia-Mediated Immune Escape in Cancer

“…Hypoxia was shown to decrease T-cell survival (29), and incubation of na€ ve T cells under hypoxia decreases their secretion of the trophic cytokine IL2 in a HIF1-dependent manner (30). CD4 þ and CD8 þ T cells derived from HIF1a-deficient mice exhibit increased proliferation, produce higher levels of interferon-g, and display increased antitumor responses (31).…”