Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma.
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, beta7 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.
Nummer
Daniel
D
T cell Tumor Immunity group, The German Cancer Research Center, INF280, 69120 Heidelberg, Germany.
Suri-Payer
Elisabeth
E
Schmitz-Winnenthal
Hubertus
H
Bonertz
Andreas
A
Galindo
Luis
L
Antolovich
Dalibor
D
Koch
Moritz
M
Büchler
Markus
M
Weitz
Jürgen
J
Schirrmacher
Volker
V
Beckhove
Philipp
P
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D015704:CD4 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002277:Carcinoma / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured / Q000276:immunology; D019040:E-Selectin / Q000502:physiology; D042783:Endothelial Cells / Q000276:immunology; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D005326:Fetal Proteins / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology; D039641:Integrin beta Chains / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D019041:L-Selectin / Q000502:physiology; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009088:Mucoproteins / Q000502:physiology; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D016201:Receptors, Lymphocyte Homing / Q000032:analysis; D013047:Specific Pathogen-Free Organisms; D018874:Spheroids, Cellular; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014183:Transplantation, Heterologous; D019139:Tumor Escape / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology; D020410:Activated-Leukocyte Cell Adhesion Molecule
D015703:Antigens, CD; D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D019040:E-Selectin; D005326:Fetal Proteins; D007136:Immunoglobulins; D039641:Integrin beta Chains; D053645:Interleukin-2 Receptor alpha Subunit; D019041:L-Selectin; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C504265:MADCAM1 protein, human; C091368:integrin beta7