Tumor Secretion of VEGF Induces Endothelial Cells to Suppress T cell Functions Through the Production of PGE2

Abstract

Summary Endothelial cells are potent regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. Previous studies by our laboratory showed that exposure to Lewis lung carcinoma (LLC)-secreted products induced endothelial cells to suppress T-cell functions in vitro. The current studies examined in vitro and in vivo the mechanism by which tumors induce the formation of suppressor endothelial cells and the means by which suppressor endothelial cells disrupt T-cell functions. In vitro studies demonstrated that inhibition of tumor-derived VEGF with neutralizing antibodies or treatment of endothelial cells with the VEGF receptor tyrosine kinase inhibitor, SU5416, prevented endothelial cells from being induced to suppress T-cell functions. Treatment of tumor-bearing mice with SU5416 blocked the development of endothelial cells that are suppressive to CD4+ and CD8+ T-cell functions. We next examined the role of suppressor endothelial cell-derived PGE2 in the inhibition of T-cell functions. Abrogation of endothelial cell PGE2 production in vitro with indomethacin prevented tumor-conditioned media from stimulating endothelial cell production of immune inhibitory activity toward T-cell functions. Similar treatment of endothelial cells from lungs of tumor-bearing mice blocked their capacity to produce T-cell-inhibitory mediators. These studies demonstrate that tumor-derived VEGF induces endothelial cells to upregulate production of PGE2 which, in turn, leads to suppression of T-cell functions.

PGE2-Induced CXCL12 Production and CXCR4 Expression Controls the Accumulation of Human MDSCs in Ovarian Cancer Environment

“…However, at present, we cannot exclude the possibility that MDSCs or MDSC-precursors are attracted into tumor microenvironment via alternative pathway and tumor-produced PGE 2 induces CXCR4 expression and MDSC retention in the CXCL12-enriched tumor environment. Although tumor cells themselves or tumor-associated stromal cells (e.g., fibroblasts (22), mesothelial cells (28), and vascular endothelial cells (29) may overproduce PGE 2 spontaneously (see Supplementary Fig. S2 for the variable levels of PGE 2 production by the non-MDSC component of ovarian cancer ascites), an alternative possibility is that tumor cell-derived factors, for example mucins in the initial induction of the first wave of COX2 expression in infiltrating monocytic cells, as proposed in the colorectal cancer system (30).…”

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

“…More difficult to explain is the underlying cause for the more rapid decay in this immune activity in mice receiving PD‐1 antibody treatment compared to the mice receiving control treatment. It is important to note that, in the HNSCC environment, there are multiple mechanisms contributing to the immune dysfunction including inhibitory mediators such and PGE 2 produced directly by the tumor cells as well as tumor‐induced immune inhibitory cells such as Treg, MDSC and the less mature CD34 + progenitor cells, infiltrating macrophages and endothelial cells 10, 11, 12, 13, 14. Studies have not, however, been conducted to determine at what point and in what sequence during progression of premalignant oral lesions to HNSCC these various inhibitory mediators and cells overcome the immune defenses.…”

“…These include tumor production of immune inhibitory mediators and tumor induction of host immune suppressor cells. Among the immune suppressive cells induced by HNSCC are Treg, inhibitory tumor‐associated macrophages and fibroblasts, myeloid‐derived suppressor cells (MDSC) and the less mature CD34 + progenitor cells 10, 11, 12, 13, 14. More recently, attention has focused on mechanisms involving activation of immune checkpoint signaling such as through PD‐1 ligand and its PD‐1 receptor.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Prostaglandin E 2 (PGE 2 ) directly suppresses various immune cells such as macrophages, neutrophils, Th1, CTL and NK cells, while it promotes Th2, Th17 and regulatory T cell responses as well as the development of tumor-associated suppressive macrophages [93,[100][101][102][103]. The Th17-promoting activity of PGE 2 is related to its ability to suppress the production of the Th17-inhibitory IL-12, while enhancing the Th17-supporting IL-23 secretion by dendritic cells [104].…”