Sialyltransferase Inhibitor Ac53FaxNeu5Ac Reverts the Malignant Phenotype of Pancreatic Cancer Cells, and Reduces Tumor Volume and Favors T-Cell Infiltrates in Mice

Abstract

Hypersialylation is a feature of pancreatic ductal adenocarcinoma (PDA) and it has been related to tumor malignancy and immune suppression. In this work, we have evaluated the potential of the sialyltransferase inhibitor, Ac53FaxNeu5Ac, to decrease tumor sialoglycans in PDA and to revert its malignant phenotype. Sialoglycans on PDA cells were evaluated by flow cytometry, and the functional impact of Ac53FaxNeu5Ac was assessed using E-selectin adhesion, migration, and invasion assays. PDA tumors were generated in syngeneic mice from KC cells and treated with Ac53FaxNeu5Ac to evaluate tumor growth, mice survival, and its impact on blocking sialic acid (SA) and on the tumor immune component. Ac53FaxNeu5Ac treatment on human PDA cells decreased α2,3-SA and sialyl-Lewisx, which resulted in a reduction in their E-selectin adhesion, and in their migratory and invasive capabilities. Subcutaneous murine tumors treated with Ac53FaxNeu5Ac reduced their volume, their SA expression, and modified their immune component, with an increase in CD8+ T-lymphocytes and NK cells. In conclusion, Ac53FaxNeu5Ac treatment weakened PDA cells’ malignant phenotype, thereby reducing tumor growth while favoring anti-tumor immune surveillance. Altogether, these results show the positive impact of reducing SA expression by inhibiting cell sialyltransferases and open the way to use sialyltransferase inhibitors to target this dismal disease.

Sialylation: A Cloak for Tumors to Trick the Immune System in the Microenvironment

“…In a study on pancreatic ductal adenocarcinoma, treatment with Ac 5 3FaxNeu5Ac resulted in the inhibition of the tumor cell production of α2,3-sialic acid and SLe X -modified glycans, leading to reduced adhesion of tumor cells to selectin. Subsequent animal experiments demonstrated that sialic acid inhibition significantly modified the composition of immune cells in the tumor microenvironment by increasing the proportion of CD8 + cells and NK cells, which facilitated the restoration of tumor immune surveillance [ 153 ]. However, the use of 3Fax-Neu5Ac as a global inhibitor of sialyltransferase may affect sialic acid metabolism in other normal organs and has been shown to be toxic to the liver and kidneys when used in large amounts in vivo [ 154 ].…”