Sialyl-Tn-positive tumour-derived extracellular vesicles impair dendritic cell function via horizontal transfer of glycans

The sialyl-Tn (STn) glycan antigen is aberrantly expressed in a subset of triple-negative breast cancer (TNBC) and is associated with poor prognosis and immunosuppressive microenvironment. Tumour-derived extracellular vesicles (TDEVs) are emerging regulators of immune escape however the role of glycan-mediated mechanisms remains elusive. Aberrant glycosylation is a hallmark of cancer that extends to TDEVs, yet how tumour-associated glycans within EV cargo modulate cell function remains poorly understood. Here we used engineered MDA-MB-231 TNBC cells to overexpress the glycosyltransferase ST6GalNAc-I, generating STn-positive cells whose EVs were enriched in STn (STn ⁺ EV). The STn ⁺ EVs impaired the maturation of monocyte-derived dendritic cells (DCs), reduced antigen presentation, and diminished CD4□ and CD8□ T cell priming, alongside the expansion of regulatory T cells. DCs co-cultured with STn□ EVs display STn at their cell surface. Notably, STn ⁺ EVs transferred both STn antigen and the ST6GalNAc-I to recipient DCs. Enzymatic removal of terminal sialic acids from STn□ EVs reversed the immunosuppressive effects, confirming the STn□dependent nature of DC dysfunction.

These findings add STn to the extensive list of components of EVs’ molecular cargo that play a role in immune suppression and may contribute for developing precision medicine approaches in oncology.