Aberrant O-glycosylation Induces IL-34-Mediated Immune Remodeling and Promotes Pancreatic Cancer Progression

Abstract

The Tn antigen, a truncated O-glycan, is frequently elevated in pancreatic ductal adenocarcinoma (PDAC). Multiple therapeutic approaches targeting Tn have been developed, but they have not demonstrated clear efficacy signals in early phase clinical studies. Improving Tn-targeted strategies in PDAC will require both overcoming the immunosuppressive tumor microenvironment and defining pathways by which truncated O-glycans promote growth and immune evasion. Here, we showed that Tn reshapes the tumor immune landscape of PDAC. Expression of Tn antigen on PDAC cells enhanced proliferation in vitro and tumor growth in vivo. Tn expression remodeled the immune microenvironment, skewing tumor-associated macrophages toward M2-like phenotypes, reducing cross-presenting dendritic cells, and expanding myeloid-derived suppressor cells (MDSCs). Single-cell RNA sequencing confirmed expansion of MDSCs and downregulation of antigen processing and presentation in the immune cell infiltrate of Tn+ tumors. Tumor-intrinsic transcriptomic analyses revealed activation of TNF-α/NF-κB signaling and induction of IL-34, a cytokine linked to monocyte survival and differentiation in Tn antigen expressing tumors. Additionally, high Tn expression in both organoids derived from pancreatic cancer patients and in PDAC mouse models was associated with increased IL-34 expression. Genetic deletion of Il34 in PDAC cells attenuated Tn-driven tumorigenesis and reduced MDSC infiltration, while recombinant IL-34 promoted myeloid cell differentiation and proliferation in vitro. Together, these findings establish a glyco-immune-cytokine axis in which truncated O-glycans contribute to IL-34-mediated immunosuppression, providing mechanistic insight and potential therapeutic targets in PDAC.