DNA methyltransferase 1 correlates with immune modulation in pancreatic neuroendocrine tumors.

Epigenetic regulation is a key driver of pancreatic neuroendocrine tumors (PNETs), yet the interplay between epigenetics and immune infiltration in the PNET tumor microenvironment remains poorly understood. This study investigates associations between epigenetic regulators and immune markers in PNETs to evaluate the potential for a combination of epigenetic-targeted therapy and immunotherapy. Immunohistochemical staining was performed on specimens from twenty-five Grade 1 or Grade 2 PNET patients, along with matched adjacent benign controls from each individual. Quantification was conducted using ImageJ software, followed by statistical analysis to assess correlations between epigenetic regulation and immune modulation. DNA methyltransferase 1 (DNMT1) was significantly upregulated in PNET samples, positively correlated with higher tumor grades and negatively correlated with 5-hydroxymethylcytosine (5-HMC) levels. Overexpression of DNMT3A and DNMT3B was also observed. Additionally, immune markers such as CD3, CD8, CCL5, and NFκB were significantly elevated, with CCL5 showing a grade-dependent increase. Interestingly, while PD-L2 was upregulated in tumors, there were no differences in the expression levels of PD-L1 and FOXP3 between PNET and adjacent benign controls. Additionally, DNMT1 expression positively correlated with Ki67, CD3, PD-L2, and CCL5 while inversely correlating with Menin. These findings suggest DNMT1 plays a significant role in immune modulation during PNET progression, highlighting the potential of combining DNMT1 inhibitors with immune checkpoint blockade as a therapeutic strategy to enhance outcomes for PNET patients.