TY - JOUR
T1 - Galectin-3 shapes antitumor immune responses by suppressing CD8 T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells
AU - Kouo, Theodore
AU - Huang, Lanqing
AU - Pucsek, Alexandra B.
AU - Cao, Minwei
AU - Solt, Sara
AU - Armstrong, Todd
AU - Jaffee, Elizabeth
N1 - Funding Information:
Grant Support This work was funded NIH grants SPORE (P50CA062924) and R01CA184926. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/4
Y1 - 2015/4
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-14-0150
DO - 10.1158/2326-6066.CIR-14-0150
M3 - Article
C2 - 25691328
AN - SCOPUS:84962221817
SN - 2326-6066
VL - 3
SP - 412
EP - 423
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 4
ER -