Role of endothelial cells in a novel mechanism of tumor-induced immune suppression.

摘要

The immune system serves as the final natural defense against tumor development. However, tumors possess numerous mechanisms by which they can suppress anti-tumor immune responses. Endothelial cells are potent regulators of immune cell functions, though their role in modulating immune functions in the tumor microenvironment remains unclear. It was hypothesized that tumors skew endothelial cells to disrupt immune cell functions. Studies testing this hypothesis determined that murine Lewis lung carcinoma (LLC)-secreted products diminished endothelial cells' ability to stimulate NK cell activation, disrupted T-cell functions and reduced macrophage phagocytosis in vitro. In the next series of studies, the ability of tumors to induce the formation of suppressor endothelial cells in vivo was investigated. Endothelial cells were isolated from the lungs of normal or tumor-bearing mice and examined for their ability to modulate immune cell functions. Compared to treatment with supernatants from normal lung endothelial cells, supernatants from endothelial cells isolated from tumor-bearing lungs diminished T-cell, NK cell and macrophage activities. The mechanisms by which suppressor endothelial cells were induced and the means by which they suppressed immune cell functions were examined. These studies demonstrated that inhibition of tumor-secreted VEGF in vitro blocked the capacity of the tumor cells to induce endothelial cells that disrupt T-cell functions. Moreover, endothelial cells isolated from the lungs of tumor-bearing mice and treated with the VEGF receptor tyrosine kinase inhibitor, SU5416, were not disruptive of T-cell functions. Inhibition of endothelial cell production of PGE2 with indomethacin in vitro and in vivo also blocked the ability of tumor-exposed endothelial cells to disrupt T-cell functions. In addition to studies with a murine tumor model, the ability of human oral squamous cell carcinoma cells (OSCC) to induce the formation of suppressor endothelial cells was investigated. These studies supported those with the mouse model by showing that OSCC-derived VEGF skewed endothelial cells to downregulate T-cell cytokine production, proliferation and cytotoxic mediator production. Together, these studies identify a novel mechanism of tumor-induced immune suppression through the induction of immune suppressive endothelial cells.