α2,6-linked sialic acid serves as a high-affinity receptor for cancer oncolytic virotherapy with Newcastle disease virus

Newcastle disease virus (NDV) has been applied to oncolytic virotherapy for decades due to its naturally oncolytic property. In spite of the substantiation of the sialic acid receptors of NDV on host cells, knowledge of preference of sialic acid linkage in viral attachment and oncolytic effect is lacking and imperative to be elucidated. Surface plasmon resonance analysis and competitive inhibition with sialylated glycan receptor analogues were used to determine the affinity and the preference of sialic acid receptor. Treatments of sialyltransferase inhibitors and linkage-specific sialidases and transfection with sialyltransferase expression vector were performed to regulate sialic acids levels. We demonstrated that sialic acid was essential for NDV binding and infection of tumor cells. alpha 2,6-linked sialic acid served as a high-affinity receptor for NDV and the ST6Gal I sialyltransferase that synthesizes alpha 2-6 linkage of sialylated N-linked glycans in CHO-K1 cells promoted NDV binding and cytopathic effect. More importantly, an enhanced antitumor effect of NDV on aggressive SW620 colorectal carcinoma cells with high-level of cell surface alpha 2,6-sialylation, but not SW480 cells with relative low-level of alpha 2,6-sialylation, was observed both in vitro and in vivo. The study provides evidence of optimized therapeutic strategy in oncolytic virotherapy via partly defining alpha 2,6-sialylated receptor as a "cellular marker" for NDV.