L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression
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L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression. / Grage-Griebenow, Evelin; Jerg, Elfi; Gorys, Artur; Wicklein, Daniel; Wesch, Daniela; Freitag-Wolf, Sandra; Goebel, Lisa; Vogel, Ilka; Becker, Thomas; Ebsen, Michael; Röcken, Christoph; Altevogt, Peter; Schumacher, Udo; Schäfer, Heiner; Sebens, Susanne.
In: MOL ONCOL, Vol. 8, No. 5, 02.04.2014, p. 982-997.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression
AU - Grage-Griebenow, Evelin
AU - Jerg, Elfi
AU - Gorys, Artur
AU - Wicklein, Daniel
AU - Wesch, Daniela
AU - Freitag-Wolf, Sandra
AU - Goebel, Lisa
AU - Vogel, Ilka
AU - Becker, Thomas
AU - Ebsen, Michael
AU - Röcken, Christoph
AU - Altevogt, Peter
AU - Schumacher, Udo
AU - Schäfer, Heiner
AU - Sebens, Susanne
N1 - Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
PY - 2014/4/2
Y1 - 2014/4/2
N2 - Regulatory T cell (T-reg) enrichment in the tumor microenvironment is regarded as an important mechanism of tumor immune escape. Hence, the presence of T-regs in highly malignant pancreatic ductal adenocarcinoma (PDAC) is correlated with short survival. Likewise, the adhesion molecule L1CAM is upregulated during PDAC progression in the pancreatic ductal epithelium also being associated with poor prognosis. To investigate whether L1CAM contributes to enrichment of T-regs in PDAC, human CD4(+)CD25(+)CD127(-)CD49d(-) T-regs and CD4(+)CD25(-) T-effector cells (T-effs) were isolated by magnetic bead separation from blood of healthy donors. Their phenotype and functional behavior were analyzed in dependence on human premalignant (H6c7) or malignant (Panc1) pancreatic ductal epithelial cells, either exhibiting or lacking L1CAM expression. T cells derived from blood and tumors of PDAC patients were analyzed by flow cytometry and findings were correlated with clinical parameters. Predominantly T-regs but not T-effs showed an increased migration on L1CAM expressing H6c7 and Panc1 cells. Whereas proliferation of T-regs did not change in the presence of L1CAM, T-effs proliferated less, exhibited a decreased CD25 expression and an increased expression of CD69. Moreover, these T-effs exhibited a regulatory phenotype as they inhibited proliferation of autologous T cells. Accordingly, CD4(+)CD25(-)CD69(+) T cells were highly abundant in PDAC tissues compared to blood being associated with nodal invasion and higher grading in PDAC patients. Overall, these data point to an important role of L1CAM in the enrichment of immunosuppressive T cells in particular of a CD4(+)CD25(-)CD69(+)-phenotype in PDAC providing a novel mechanism of tumor immune escape which contributes to tumor progression.
AB - Regulatory T cell (T-reg) enrichment in the tumor microenvironment is regarded as an important mechanism of tumor immune escape. Hence, the presence of T-regs in highly malignant pancreatic ductal adenocarcinoma (PDAC) is correlated with short survival. Likewise, the adhesion molecule L1CAM is upregulated during PDAC progression in the pancreatic ductal epithelium also being associated with poor prognosis. To investigate whether L1CAM contributes to enrichment of T-regs in PDAC, human CD4(+)CD25(+)CD127(-)CD49d(-) T-regs and CD4(+)CD25(-) T-effector cells (T-effs) were isolated by magnetic bead separation from blood of healthy donors. Their phenotype and functional behavior were analyzed in dependence on human premalignant (H6c7) or malignant (Panc1) pancreatic ductal epithelial cells, either exhibiting or lacking L1CAM expression. T cells derived from blood and tumors of PDAC patients were analyzed by flow cytometry and findings were correlated with clinical parameters. Predominantly T-regs but not T-effs showed an increased migration on L1CAM expressing H6c7 and Panc1 cells. Whereas proliferation of T-regs did not change in the presence of L1CAM, T-effs proliferated less, exhibited a decreased CD25 expression and an increased expression of CD69. Moreover, these T-effs exhibited a regulatory phenotype as they inhibited proliferation of autologous T cells. Accordingly, CD4(+)CD25(-)CD69(+) T cells were highly abundant in PDAC tissues compared to blood being associated with nodal invasion and higher grading in PDAC patients. Overall, these data point to an important role of L1CAM in the enrichment of immunosuppressive T cells in particular of a CD4(+)CD25(-)CD69(+)-phenotype in PDAC providing a novel mechanism of tumor immune escape which contributes to tumor progression.
U2 - 10.1016/j.molonc.2014.03.001
DO - 10.1016/j.molonc.2014.03.001
M3 - SCORING: Journal article
C2 - 24746181
VL - 8
SP - 982
EP - 997
JO - MOL ONCOL
JF - MOL ONCOL
SN - 1574-7891
IS - 5
ER -