de Oliveira, B. R. | bioRxiv Science

bioRxiv2026

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{square} and CD8{square} T cell priming, alongside the expansion of regulatory T cells. DCs co-cultured with STn{square} 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{square} EVs reversed the immunosuppressive effects, confirming the STn{square}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.

immunology↗

bioRxiv2023

N-Acetylcysteine alters disease progression and increases Janus Kinase mutation frequency in a mouse model of precursor B cell acute lymphoblastic leukemia

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-Cre{Delta}PB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence. Treatment of Mb1-Cre{Delta}PB mice with NAC in drinking water significantly reduced the frequency of CD19+ pre-B ALL cells infiltrating the thymus at 11 weeks of age. However, treatment with NAC did not reduce leukemia progression or increase survival by median 16 weeks of age. NAC significantly altered gene expression in leukemias in treated mice. Mice treated with NAC had increased frequencies of activating mutations in genes encoding Janus Kinases 1 and 3. In particular, frequencies of Jak3 R653H mutations were increased in mice treated with NAC compared to control drinking water. NAC opposed oxidization of PTEN protein ROS in cultured leukemia cells. These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies.

cancer biology↗