title: L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression.
abstract: 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.
authors.affiliation: Group Inflammatory Carcinogenesis, Institute for Experimental Medicine, UKSH Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
authors.forename: Evelin
authors.initials: E
authors.lastname: Grage-Griebenow
authors.affiliation: Group Inflammatory Carcinogenesis, Institute for Experimental Medicine, UKSH Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
authors.forename: Elfi
authors.initials: E
authors.lastname: Jerg
authors.affiliation: Group Inflammatory Carcinogenesis, Institute for Experimental Medicine, UKSH Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
authors.forename: Artur
authors.initials: A
authors.lastname: Gorys
authors.affiliation: Institute for Anatomy and Experimental Morphology, UKE Hamburg Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wicklein
authors.affiliation: Institute of Immunology, UKSH Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
authors.affiliation: Institute of Medical Informatics and Statistics, UKSH Campus Kiel, Brunswiker Str. 10, 24105 Kiel, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Freitag-Wolf
authors.affiliation: Group Inflammatory Carcinogenesis, Institute for Experimental Medicine, UKSH Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Goebel
authors.affiliation: Department of Surgery, Community Hospital Kiel, Chemnitzstr. 33, 24116 Kiel, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Vogel
authors.affiliation: Department of General and Thoracic Surgery, UKSH Campus Kiel, Arnold-Heller-Str. 3, Building 18, 24105 Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.affiliation: Institute of Pathology, Community Hospital Kiel, Chemnitzstr. 33, 24116 Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ebsen
authors.affiliation: Institute of Pathology, UKSH Campus Kiel, Arnol-Heller-Str. 3, Building 14, 24105 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Department of Translational Immunology D015, German Cancer Research Center, Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
authors.affiliation: Institute for Anatomy and Experimental Morphology, UKE Hamburg Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.affiliation: Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH Campus Kiel; Arnold-Heller-Str. 3, Building 6, 24105 Kiel, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Schäfer
authors.affiliation: Group Inflammatory Carcinogenesis, Institute for Experimental Medicine, UKSH Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany. Electronic address: mueerkoe@1med.uni-kiel.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Sebens
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology*; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D039842:Neural Cell Adhesion Molecule L1 / Q000276:immunology*; D010183:Pancreatic Ducts / Q000276:immunology / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D039842:Neural Cell Adhesion Molecule L1
keywords: CD171; Immune evasion; Malignant progression; Pancreatic adenocarcinoma; Regulatory T cells; Tumor stroma
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