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 factor–secretingallogeneicPDAvaccinedevelopedneutralizingantibodies to galectin-3 after immunization. We show that galectin-3 binds activated antigen-committed CD8 þ T cells only in the tumor microenvironment. Galectin-3–deficient mice exhibit improved CD8 þ 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 ofCD8 þ Tcellsinvitro.Lastly, galectin-3–deficientmice have elevated levels of circulating plasmacytoid dendritic cells, which are superior to conventional dendritic cells in activating CD8 þ T