<p>Predicted activation of TNFα, IFNγ, and IL-6 signaling pathways in the KO/KO CD8<sup>+</sup> T cells vs. WT/WT CD8<sup>+</sup> T cells. Analyses was conducted using Ingenuity IPA software.</p>
ARTICLE 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. Cancer Immunol Res; 3(4); 412–23. ©2015 AACR.
