Tumors skew endothelial cells to disrupt NK cell, T-cell and macrophage functions

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.

Endothelial cells were pre-treated with LLC tumor-conditioned medium (Endo(T-sup)) for 24 h. Control endothelial cells that were exposed to medium (Endo(Media)) epithelial cell-conditioned medium or (Endo(Epi-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 Endo(Media), Endo(Epi-sup) or Endo(T-sup) were collected and assayed for immune modulatory products and for immune modulatory activity.

Supernatant from Endo(T-sup) contained increased levels of PGE2, IL-6 and VEGF as compared to Endo(Media) and Endo(Epi-sup) controls. NK cell activity, as measured by TNF-alpha and IFN-gamma secretion, was increased following exposure to media conditioned by Endo(Media) and Endo(Epi-sup) Exposure of NK cells to supernatants of Endo(T-sup), also increases TNF-alpha and IFN-gamma secretion, but to a lesser extent than by Endo(Media) and Endo(Epi-sup). Examination of macrophage functions demonstrated that supernatant from Endo(T-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 Endo(T-sup) were examined. IFN-gamma production by CD8+ T-cells was reduced after exposure to Endo(T-sup)-conditioned medium, as compared to cells treatments with medium or control conditioned medium. Production of IFN-gamma by CD4+ T-cells exposed to Endo(T-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.