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 kD lectin that modulates T-cell responses through several mechanisms including apoptosis, T-cell receptor (TCR) cross-linking, and TCR down-regulation. We found patients with pancreatic ductal adenocarcinoma (PDA) responding to a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDA vaccine developed post immunization neutralizing antibodies to galectin-3. We show that galectin-3 binds activated antigen-committed CD8+ T cells only in the tumor microenvironment (TME). 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 (pDC), which are superior to conventional dendritic cells (cDC) in activating CD8+ T cells. Thus, inhibiting galectin-3 in conjunction with CD8+ T cell-directed immunotherapies should enhance the tumor-specific immune response.

Immune Checkpoint Inhibitor Combinations in Solid Tumors: Opportunities and Challenges

“…It has been demonstrated that LAG3 can bind to MHC class II molecules and galectin-3 with functional consequences [24]. Interaction of LAG3-MHC class II allows inhibition of CD8 + effector T cells and enhancement of CD4 + Treg cells.…”

Mini-intronic plasmid vaccination elicits tolerant LAG3+CD8+T cells and inferior antitumor responses

“…In fact, it has recently been shown that galectin-3 binds to LAG3 on terminally differentiated CD8 C T cells only in the tumor microenvironment to cause their dysregulation. 47 …”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…35 LAG3 is also required for T reg to maintain the suppressive function. Moreover, galectin-3 and L-selectin have been discovered as the ligands for LAG3 expressed on CD8 þ T cells to inhibit the antitumor response, 36,37 or other possible ligands, not defined. Still, more clear mechanisms regarding LAG3 in the tumor microenvironment are needed to be clarified.…”