title: Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells.
abstract: Galectin-3 is a 31-kDa lectin that modulates T-cell responses through several mechanisms, including apoptosis, T-cell receptor (TCR) cross-linking, and TCR downregulation. We found that patients with pancreatic ductal adenocarcinoma (PDA) who responded to a granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDA vaccine developed neutralizing antibodies to galectin-3 after immunization. We show that galectin-3 binds activated antigen-committed CD8(+) T cells only in the tumor microenvironment. Galectin-3-deficient mice exhibit improved CD8(+) T-cell effector function and increased expression of several inflammatory genes. Galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3-mediated suppression of CD8(+) T cells in vitro. Lastly, galectin-3-deficient mice have elevated levels of circulating plasmacytoid dendritic cells, which are superior to conventional dendritic cells in activating CD8(+) T cells. Thus, inhibiting galectin-3 in conjunction with CD8(+) T-cell-directed immunotherapies should enhance the tumor-specific immune response.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. tkouo1@jhmi.edu ejaffee@jhmi.edu.
authors.forename: Theodore
authors.initials: T
authors.lastname: Kouo
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lanqing
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alexandra B
authors.initials: AB
authors.lastname: Pucsek
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Minwei
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sara
authors.initials: S
authors.lastname: Solt
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Todd
authors.initials: T
authors.lastname: Armstrong
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. tkouo1@jhmi.edu ejaffee@jhmi.edu.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jaffee
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000628:therapy*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D019496:Cancer Vaccines; D037502:Galectin 3; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein