Visium spatial transcriptomics analysis of sections of human PanIN and PDAC
Pancreatic ductal adenocarcinoma (PDAC) has a 5–year survival rate of 12%, largely due to late detection of the disease. PDAC arises from precursor microscopic lesions, termed pancreatic intraepithelial neoplasia (PanIN) that develop at least a decade before overt disease progression––this provides a wide window of opportunity to intercept PanIN–to–PDAC progression. However, immune interception strategies require a full understanding of the cellular architecture of PanINs and PDAC. Using spatial–omics (proteomic and transcriptomic) in treatment–naïve patients, we uncovered, for the first time, the organization of lymphoid cells into tertiary lymphoid structures (TLSs) adjacent to PanIN lesions. These were characterized by the relative lack of CD21+CD23+ B cells in comparison to more mature TLSs found near PDAC. Mature TLSs were found near invasive PDAC border, despite patients being treatment naïve. We also found that lymphoid populations in general are recruited preferentially to low–grade PanINs compared with normal tissue. Notably, PanINs harbored mostly CD4+ T cells with fewer Tregs and exhausted T cell populations, which in contrast are prominent within PDAC tumors. Peri–tumoral immune cells were also denser and enriched with naïve CD4+ T cells and central memory T cells compared with intra–tumoral populations. In all, our data show that PanIN lesions recruit lymphoid populations early on and that these lymphoid cells are capable of organizing into immature TLSs. These results thus implicate the opportunity to modulate the immune microenvironment in pre–malignant PanINs before immune exclusion and immunosuppression emerge as these lesions progress in PDAC.