Journal of the National Cancer Institute Advance Access published online on July 24, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm064
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Role of Tumor Endothelium in CD4+CD25+ Regulatory T Cell Infiltration of Human Pancreatic Carcinoma
Affiliations of authors: T cell Tumor Immunity group (DN, AB, PB) and Departments of Immunogenetics (ESP) and Cellular Immunology (VS), The German Cancer Research Center, Heidelberg, Germany; Department of Visceral Surgery, University Hospital of Heidelberg, Heidelberg, Germany (HSW, LG, DA, MK, MB, JW)
Correspondence to: Philipp Beckhove, MD, T cell Tumor Immunity group (D011), The German Cancer Research Center, INF280, 69120 Heidelberg, Germany (e-mail: p.beckhove{at}dkfz.de).
Background: Regulatory T (Treg) cells have been detected in human carcinomas and may play a role in preventing the rejection of malignant cells.
Methods: We quantified Treg cells and the expression of the addressins and the respective ligands that attract them in blood and in human pancreatic tumors and adjacent nonmalignant tissues from 47 patients. The capacity of Treg cells to adhere to and transmigrate through autologous endothelial cells was tested in vitro using spheroid adhesion assays and in vivo using a xenotransplant NOD/SCID model and in the presence and absence of antibodies to addressins. All statistical tests were two-sided.
Results: More Treg cells infiltrated pancreatic carcinomas than adjacent nonmalignant pancreatic tissues (120 cells per mm2 versus 80 cells per mm2, difference = 40 cells per mm2, 95% confidence interval [CI] = 21.2 cells per mm2 to 52.1 cells per mm2; P<.001). In contrast to conventional CD4+ T cells, more blood-derived Treg cells adhered to (1.0% versus 5.2%, difference = 4.2%, 95% CI = 2.7% to 5.6%; P<.001) and transmigrated through (3332 cells versus 4976 cells, difference = 1644 cells, 95% CI = 708 cells to 2580 cells; P = .008) autologous tumor-derived endothelial cells in vitro and in vivo (458 cells versus 605 cells, difference = 147 cells, 95% CI = 50.8 to 237.2 cells; P = .04). Tumor-derived endothelial cells expressed higher levels of addressins—including mucosal adressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD62-E, and CD166—than endothelial cells from normal tissue. Experiments using antibodies to addressins showed that transmigration was mediated by interactions of addressins, including MAdCAM-1, VCAM-1, CD62-E, and CD166 with their respective ligands, 
7 integrin, CD62L, and CD166, which were expressed specifically on Treg cells.
Conclusions: Tumor-induced expression of addressins on the surface of endothelial cells allows a selective transmigration of Treg cells from peripheral blood to tumor tissues.
| CONTEXT AND CAVEATS Prior knowledge Regulatory T cells may help tumor cells escape detection by the host's immune defense system. Study design Patient tumor and normal samples and in vitro and in vivo models were used to examine T-cell infiltration into pancreatic tumors and the mechanisms involved. Contribution More regulatory T cells were identified in pancreatic tumor samples than adjacent normal tissues; similar results were found in the in vitro and in vivo models. Addressins, proteins that target regulatory T cells, were highly expressed on the surface of the tumor-derived cells and were shown to be involved in the movement of regulatory T cells from the peripheral blood to tumor tissues. Implications Tumor-induced expression of addressins is a step in the infiltration of regulatory T cells into tumor tissue. Study limitations Other possible mechanisms, such as loss of conventional T cell homing receptors’ selective induction of addressins, were not specifically studied and cannot be ruled out.
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Manuscript received January 25, 2007; revised May 22, 2007; accepted June 19, 2007.
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J Natl Cancer Inst 2007 99: 1137.
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