期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 57, 期 7, 页码 951-961出版社
SPRINGER
DOI: 10.1007/s00262-007-0425-x
关键词
endothelial cell; suppressor; tumor; immune suppression; Lewis lung carcinoma
资金
- NCI NIH HHS [R01 CA 97813, R01 CA085266, R01 CA085266-06, R01 CA128837, R01 CA097813, R01 CA 85266, R01 CA128837-05] Funding Source: Medline
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 (Endo(T-sup)) for 24 h. Control endothelial cells that were exposed to medium (Endo(Media)) or epithelial cell-conditioned medium (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. Results Supernatant from Endo(T-sup) contained increased levels of PGE(2), 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(T-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 PGE(2). 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.
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