Spatial IgA Plasma Cell Niches Drive Anti-Tumor Immunity in Pancreatic Cancer 2307077

Abstract

Abstract Introduction Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among major cancers, with a five-year survival rate below 10%. The tumor microenvironment (TME) strongly shapes immune responses, yet key immune cell interactions remain unclear. Plasma cells are abundant in PDAC tumors, but their roles in anti-tumor immunity are not well defined. We aimed to determine how spatially organized plasma cell populations influence immune cell function and patient survival within the PDAC TME. Methods We integrated two spatial transcriptomics cohorts with tumor and normal tissues from 71 PDAC patients, representing a large-scale spatial systems immunology analysis of plasma cells. We defined plasma cell niches within the TME and integrated these spatial features with TCGA PDAC data to test associations with patient survival. We modeled spatial cell-cell communication to link immune interactions with clinical outcomes and compared ligand-receptor signaling and spatial gene regulatory networks between IgA/M and IgG plasma cell niches. Results Plasma cell abundance increased with advanced lymph node metastasis stages (pN). IgA/M and IgG plasma cells formed distinct spatial niches in the PDAC TME. IgA/M niches were enriched for nearby T cells, NK cells, and antigen-presenting myeloid cells and were associated with stronger T cell cytotoxicity, clonal expansion, and longer patient survival. Tumor-derived LINE1 was associated with activation of MAF and IRF4 programs in IgA/M cells, which promoted TIMP1—CD63 signaling to myeloid cells and enhanced antigen presentation. Conclusion Distinct plasma cell niches actively shape cellular immune responses in the PDAC TME. IgA/M plasma cells support coordinated anti-tumor activity by T cells, NK cells, and myeloid cells and are linked to improved patient survival. These findings establish spatial plasma cell organization as a central regulator of tumor immunity and a promising target for immune-based strategies in pancreatic cancer. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)