Sialyltransferase Inhibitor Ac(5)3F(ax)Neu5Ac Reverts the Malignant Phenotype of Pancreatic Cancer Cells, and Reduces Tumor Volume and Favors T-Cell Infiltrates in Mice

SIMPLE SUMMARY: An increase of sialic acid in the cancer cells’ surface is a hallmark of tumours, including pancreatic cancer, and it has been related to tumour malignancy and immune suppression. In this work, we have assessed for the first time the potential of the sialyltransferase inhibitor, Ac(5)3F(ax)Neu5Ac, to reduce tumor sialylation in pancreatic cancer and to revert its malignant phenotype. We have shown that Ac(5)3F(ax)Neu5Ac treatment on human pancreatic cancer cells decreased their sialic acid, reduced their E-selectin adhesion—the prior step to tumour extravasation—and their migration and invasion capabilities. In addition, subcutaneous pancreatic tumours generated on immunocompetent mice that were treated with Ac(5)3F(ax)Neu5Ac showed a reduced growth and increased tumour infiltrating lymphocytes. These results show that the targeting of tumour sialoglycans in pancreatic cancer reverts its malignant phenotype and favours anti-tumour immune surveillance, which opens the way to use sialyltransferase inhibitors as a novel therapeutic strategy against this dismal disease. 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, Ac(5)3F(ax)Neu5Ac, 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 Ac(5)3F(ax)Neu5Ac was assessed using E-selectin adhesion, migration, and invasion assays. PDA tumors were generated in syngeneic mice from KC cells and treated with Ac(5)3F(ax)Neu5Ac to evaluate tumor growth, mice survival, and its impact on blocking sialic acid (SA) and on the tumor immune component. Ac(5)3F(ax)Neu5Ac treatment on human PDA cells decreased α2,3-SA and sialyl-Lewis(x), which resulted in a reduction in their E-selectin adhesion, and in their migratory and invasive capabilities. Subcutaneous murine tumors treated with Ac(5)3F(ax)Neu5Ac reduced their volume, their SA expression, and modified their immune component, with an increase in CD8(+) T-lymphocytes and NK cells. In conclusion, Ac(5)3F(ax)Neu5Ac 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.