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.
Osteopontin （OPN）, a multifunctional glycoprotein, has three transcripts that have distinct roles in tumors in vitro. Whether OPN transcripts have different functions in tumor processes in vivo is unclear. It has been reported that immune cell-derived OPN can promote tumor formation. We propose a hypothesis that tumor-derived OPN may facilitate tumor immune escape by affecting immune cell differentiation and function. In this study, we constructed lentiviral expression vectors of OPN transcripts and transfected them into the MCF-7 cell line. MCF-7 cells transfected with OPN transcripts were injected into the armpit of nude mice, and tumor growth was monitored. The results showed that all OPN transcripts promoted local tumor formation, but that there was no significant difference among transcripts. We also investigated the effect of the OPN expressed by tumor cells on monocyte differentiation by coculturing monocytes with tumor supernatant. We found OPN-c upregulated CD163 levels compared with OPN-a and OPN-b; however, none of the transcripts affected HLA-DR and CD206 levels. All OPN transcripts significantly inhibited TNF-α and enhanced IL-10 production by monocytes. Furthermore, we found that the overexpression of OPN transcripts significantly upregulated TGF-β1 and MCP-1 production by tumor cells. Using neutralizing antibody and recombinant cytokines, we found that OPN overexpressed by tumor cells regulates the production of TNF-α and IL-10 by monocytes partly via MCP-1 and TGF-β1, respectively. Collectively, our results show that OPN transcripts have no distinct role in breast cancer formation in vivo. We also demonstrate that OPN regulates the alternative activation of monocytes via TGF-β1 and MCP-1, which may represent an additional mechanism for tumor immune escape.
