Immune cell distribution and DNA methylation signatures differ between tumor and stroma enriched compartment in pancreatic ductal adenocarcinoma

ABSTRACT: Background: The presence of abundant tumor stroma is a prominent characteristic of pancreatic ductal adenocarcinomas (PDAC) that potentially influences disease progression and therapy response. This study aims to investigate immune cell infiltration and epigenetic profiles in tumor cell enriched (“Tumor”) and stroma cell enriched (“Stroma”) regions within human PDAC tissue samples to identify regional-specific genetic alterations as a basis for novel drug target development. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples were obtained initially from 15 patients who underwent PDAC resection. Tumor and Stroma regions were separately assessed for their immune cell composition by using immunohistochemistry (IHC) and epigenetic modifications based on DNA methylation obtained by Infinium MethylationEPIC microarrays. A tissue microarray cohort of additional 65 PDAC patients was included for validation of IHC findings and survival analysis. Results: By comparing Tumor and Stroma defined regions of PDAC tumors, we identified 25,410 differentially methylated positions (DMPs) distributed across 6,963 unique genes. Pathway enrichment analysis using the top 2,000 DMPs that were either hyper- or hypomethylated, indicated that immune response pathways and the estrogen receptor pathway are epigenetically dysregulated in Tumor and Stroma regions, respectively. In terms of immune cell infiltration, we observed overall low levels of T cells in both regions. In Tumor regions however, occurrence of tumor-associated macrophages (TAMs) was higher than in Stroma regions (p=0.02) concomitant with a dualistic distribution that stratifies PDAC patients into those with high and low TAM infiltration. By categorizing TAM levels into quartiles, our analysis revealed that PDAC patients with more than 1,515 TAMs per mm², representing the upper quartile, exhibited significantly shorter overall survival (p=0.036). Conclusions: Our data suggest that variations in inflammatory characteristics between the Tumor and Stroma defined compartments of PDAC may primarily stem from the presence of macrophages rather than lymphocytes. The abundance of TAMs within regions enriched with tumor cells correlates with patient survival, underscoring the potential significance of exploring therapeutic interventions targeting TAMs. Furthermore, directing attention towards the estrogen receptor pathway represents a promising strategy to address the stroma cell component within the PDAC tumor microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244696 | GEO | 2025/01/24

REPOSITORIES: GEO