胰腺腺癌免疫肿瘤微环境由差异性miRNA表达所塑造

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with poor prognosis and advanced stage at diagnosis. The tumor microenvironment (TME) plays a role in driving aggressive, treatment-resistant PDAC subtypes. This study explores miRNAs' role in modulating the immune cell composition of the PDAC TME. Methods: The Database of Differentially Expressed microRNAs in Cancer was queried for miRNAs with log2 fold-change ≥3.5 or ≤-3.5 between PDAC and normal pancreas. miRNA and predicted target mRNA expression in neoadjuvant-treated PDAC samples was profiled using Nanostring nCounter. Patient and disease characteristics, miRNA target prediction, biologic pathways, immune infiltration, and survival were analyzed to identify associations with aggressive, treatment-resistant disease. Results: Differentially expressed miRNAs were analyzed using Nanostring nCounter. Principal component analysis revealed two sample clusters: one with younger patients, high nodal stage, frequent positive surgical margins, and poor neoadjuvant treatment response; the other with less advanced disease features and better neoadjuvant treatment response. 14 differentially expressed miRNAs and 31 mRNA targets were identified. These were predicted to activate cytokine signaling, neutrophil degranulation, phagosome formation, IL-27 signaling, and tumor microenvironment pathways on Qiagen Ingenuity Pathway Analysis. Survival-congruent expression, defined by inverse hazard ratio between miRNAs and target mRNAs, was observed for miR-148a-3p (targets: SLC2A1, ITGA5) and mir-193a/b-5p (target: RORC). Low miR-148a-3p levels and high miR-193a/b-5p levels were linked to short overall survival. TIMER 2.0 analysis demonstrated positive correlation between ITGA5 expression and cancer-associated fibroblasts, M2 macrophages, and regulatory T cell infiltration; global suppressive effect of SLC2A1 on immune cell infiltration; and a mixed effect of RORC on immune cell infiltration, characterized by positive correlation with neutrophil and type 1 macrophages and negative correlation with CAF, natural killer cell, and dendritic cells. Conclusion: Distinct miRNA expression profiles in neoadjuvant-treated PDAC are linked to increased inflammatory signaling and immunosuppressed TME via effect on predicted mRNA targets. A subset of miRNAs differentially expressed between advanced, treatment-resistant PDAC and treatment-responsive PDAC is predicted to influence the PDAC TME via upregulation of immune pathway signaling and effects on the TME composition. Particularly, we demonstrated that low miR-148a-3p expression in treatment-resistant PDAC facilitates ITGA5-mediated immunosuppressive cell infiltration and predicts worse survival. Together, these findings highlight miRNAs' role as critical modulators of the PDAC immune TME and clinical outcomes in PDAC.