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

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

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 s...

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Published in:Translational research : the journal of laboratory and clinical medicine Vol. 271; pp. 40 - 51
Main Authors: Tomasich, Erwin, Mühlbacher, Jakob, Wöran, Katharina, Hatziioannou, Teresa, Herac, Merima, Kleinberger, Markus, Berger, Julia Maria, Dibon, Lea Katharina, Berchtold, Luzia, Heller, Gerwin, Bergen, Elisabeth Sophie, Macher-Beer, Andrea, Prager, Gerald, Schindl, Martin, Preusser, Matthias, Berghoff, Anna Sophie
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-09-2024
Subjects:
Epigenetics
Immune cells
Methylation
Pancreas
Stroma
CD
TAM
IM
OS
IHC
DMP
Stroma
GSEA
TMA
IQR
ER
TME
LUMP
PDAC
FDR
FFPE
IGR
ECOG
Epigenetics
Pancreas
Immune cells
Methylation
immune cells
methylation
pancreas
epigenetics
stroma
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Summary: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. By comparing those regions, 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 exhibited significantly shorter overall survival (p = 0.036). 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 may represent a promising strategy to address the stroma cell component within the PDAC tumor microenvironment.
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content type line 23
ISSN:1931-5244
1878-1810
DOI:10.1016/j.trsl.2024.05.005