Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells

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...

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Bibliographic Details
Published in:Cancer immunology research 2015-04, Vol.3 (4), p.412-423
Main Authors: Kouo, Theodore, Huang, Lanqing, Pucsek, Alexandra B, Cao, Minwei, Solt, Sara, Armstrong, Todd, Jaffee, Elizabeth
Format: Article
Language:English
Subjects:
Animals
Antigens, CD - immunology
Cancer Vaccines - immunology
Cancer Vaccines - therapeutic use
Carcinoma, Pancreatic Ductal - immunology
Carcinoma, Pancreatic Ductal - therapy
CD8-Positive T-Lymphocytes - immunology
Cell Differentiation - immunology
Dendritic Cells - immunology
Female
Galectin 3 - deficiency
Galectin 3 - genetics
Galectin 3 - immunology
Humans
Immune Tolerance
Immunophenotyping
Interferon-gamma - biosynthesis
Lymphocyte Activation - immunology
Lymphocytes, Tumor-Infiltrating - immunology
Mice, Knockout
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - therapy
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Summary: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.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-14-0150