Tumors skew endothelial cells to disrupt NK cell, T-cell and macrophage functions |
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Authors: | Jennifer K Mulligan Deanne M R Lathers M Rita I Young |
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Institution: | (1) Research Service (151), Ralph H. Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29401, USA;(2) Department of Otolaryngology, Medical University of South Carolina, Charleston, SC, USA;(3) Department of Medicine, Medical University of South Carolina, Charleston, SC, USA |
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Abstract: | Introduction Patients and mice with solid tumors, such as Lewis lung carcinoma (LLC), have defects in functions of immune effector cells.
Endothelial cells, a component of the tumor vasculature, are potential regulators of immune cell functions. Therefore, these
studies examined the impact of exposure to LLC tumor on the ability of endothelial cells to modulate immune cell functions.
Materials and methods Endothelial cells were pre-treated with LLC tumor-conditioned medium (EndoT-sup) for 24 h. Control endothelial cells that were exposed to medium (EndoMedia) or epithelial cell-conditioned medium (EndoEpi-sup). After the initial 24 h incubation, endothelial cells were washed and fresh media was added. Cells were allowed to incubate
for an additional 24 h. Supernatants from EndoMedia, EndoEpi-sup or EndoT-sup were collected and assayed for immune modulatory products and for immune modulatory activity.
Results Supernatant from EndoT-sup contained increased levels of PGE2, IL-6 and VEGF as compared to EndoMedia and EndoEpi-sup controls. NK cell activity, as measured by TNF-α and IFN-γ secretion, was increased following exposure to media conditioned
by EndoMedia and EndoEpi-sup. Exposure of NK cells to supernatants of EndoT-sup, also increases TNF-α and IFN-γ secretion, but to a lesser extent than by EndoMedia and EndoEpi-sup. Examination of macrophage functions demonstrated that supernatant from EndoT-sup decreased microbead phagocytosis and increased production of the immune suppressive mediators, IL-10 and PGE2. Lastly, T-cell responses to stimulation with anti-CD3 in the presence of supernatants from EndoT-sup were examined. IFN-γ production by CD8+ T-cells was reduced after exposure to EndoT-sup-conditioned medium, as compared to cells treatments with medium or control conditioned medium. Production of IFN-γ by CD4+ T-cells exposed to EndoT-sup was not altered.
Conclusions Taken together, these studies demonstrate that tumors skew endothelial cells to disrupt NK cell, T-cell and macrophages functions,
and represents a novel mechanism of tumor-induced immune suppression. |
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Keywords: | Endothelial cell Suppressor Tumor Immune suppression Lewis lung carcinoma |
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