Spatial Proteomics and Transcriptomics Reveal Early Immune Cell Organization in Pancreatic Intraepithelial Neoplasia

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate largely due to late detection of disease. PDAC arises from precursor microscopic lesions, termed pancreatic intraepithelial neoplasia (PanIN), that develop at least a decade before overt disease progression––this provides an opportunity to intercept PanIN–to–PDAC progression. However, immune interception strategies require a full understanding of PanIN and PDAC cellular architecture. Methods: Surgical specimens containing PanIN and PDAC lesions from a unique cohort of treatment-naïve patients with PDAC were surveyed using spatial-omics (proteomic and transcriptomic). Results: We uncovered, for the first time, the organization of lymphoid cells into tertiary lymphoid structures (TLSs) adjacent to PanIN lesions. These TLSs lack CD21+CD23+ B cells in comparison to more mature TLSs. Mature TLSs were found near the invasive PDAC border, despite patients being treatment-naïve. PanINs harbored mostly CD4+ T cells with fewer Tregs and exhausted T cells than PDAC tumors. Peri-tumoral space was enriched with naïve CD4+ and central memory T cells. Conclusions: These data show that early PanIN lesions recruit effector lymphoid populations capable of organizing into immature TLSs with few immune suppressive T cells relative to PDAC-associated TLS. These results implicate the opportunity to modulate the immune microenvironment in pre–malignant PanINs before immune exclusion and immunosuppression emerge during progression into PDACs.