Spatial proteomics and transcriptomics reveal early immune cell organization in pancreatic intraepithelial neoplasia

Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate due to late detection. PDAC arises from precursor microscopic lesions, termed pancreatic intraepithelial neoplasia (PanIN), that develop at least a decade before overt disease; this provides an opportunity to intercept PanIN-to-PDAC progression. However, immune interception strategies require full understanding of PanIN and PDAC cellular architecture. Surgical specimens containing PanIN and PDAC lesions from a unique cohort of 5 treatment-naive patients with PDAC were surveyed using spatial omics (proteomic and transcriptomic). Findings were corroborated by spatial proteomics of PanIN and PDAC from tamoxifen-inducible KPC mice. We uncovered the organization of lymphoid cells into tertiary lymphoid structures (TLSs) adjacent to PanIN lesions. These TLSs lacked CD21⁺CD23⁺ B cells compared with more mature TLSs near the PDAC border. PanINs harbored mostly CD4⁺ T cells, with fewer Tregs and exhausted T cells than PDAC. Peritumoral space was enriched with naive CD4⁺ and central memory T cells. These observations highlight the opportunity to modulate the immune microenvironment in PanINs before immune exclusion and immunosuppression emerge during progression into PDAC.