Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with a 5-year survival rate of only 12.8%, and its increasing incidence in Western countries highlights the urgent need for better early-stage detection and treatment methods. Early diagnosis significantly improves the chances of survival, but non-specific symptoms and undetectable precursor lesions pose a major challenge. To date, there are no reliable screening tools to detect PDAC at an early stage. Herpesvirus entry mediator (HVEM) has already been proposed as a prognostic marker in numerous cancer types. Therefore, we investigated the role of HVEM in PDAC. Flow cytometry was used to analyze HVEM expression in immune cells and its inhibitory receptors (CD160 and BTLA) on T-cells, as well as its subsets in the peripheral blood of 57 diagnosed PDAC patients and 17 clinical controls. In addition, survival analyses were performed within the PDAC cohort, changes in HVEM expression were analyzed in relation to clinicopathological parameters, and a correlation analysis between HVEM expression and cytokine levels of IL-6 and IL-10 was conducted. Furthermore, HVEM expression on monocytes and their subsets was evaluated as a potential prognostic marker and compared with the prognostic utility of CA19-9. We found that HVEM expression is significantly elevated on immune cells, particularly on monocytes (p < 0.0001) and their subsets, in PDAC patients, and is associated with reduced survival (p = 0.0067) and clinicopathological features such as perineural, lymphovascular, and vascular invasion. Moreover, HVEM-expressing monocytes demonstrated superior predictive value compared to CA19-9, highlighting their potential as part of a combined screening tool for PDAC. In conclusion, HVEM on monocytes could serve as a novel prognostic marker for PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune cell dysfunction and poor prognosis. CD44, a cell surface glycoprotein with multiple splice variants, has been implicated in tumor progression, but its compartment-specific roles in PDAC remain unclear. CD44 standard and variant isoform expression was analyzed in patient-derived lymph nodes (LNs) by quantitative PCR. Immune cell-specific CD44 expression was assessed by flow cytometry in LNs and peripheral blood. Soluble and exosome-associated CD44 (exo-CD44) were measured in plasma. Clinical associations and survival analyses were performed. Transcriptomic, immune infiltration, immune checkpoint, and drug sensitivity analyses were conducted using TCGA-PAAD and pharmacogenomic datasets. CD44 standard isoform expression was unchanged in PDAC LNs, whereas multiple CD44 variant isoforms (v4–v10) were significantly reduced and associated with metastatic disease and poor survival, particularly CD44v5, v6, v7, and v10. CD44 expression was enriched in CD45⁺ immune cells, with highest levels in CD4⁺ T cells in both LNs and blood. Soluble CD44 levels showed no clinical associations. In contrast, exo-CD44 levels were reduced overall in PDAC but increased in patients with distant metastasis, positive resection margins, systemic inflammation, and reduced survival. High CD44 expression was associated with advanced disease, immune cell infiltration, immune checkpoint gene expression, reduced sensitivity to gemcitabine, paclitaxel, rapamycin, and FMK, and distinct CTLA4/PD-L1 checkpoint profiles. CD44 exhibits compartment-specific regulation in PDAC, linking immune remodeling, exosome signaling, and therapeutic resistance to adverse clinical outcome.

Circulating myeloid cells are critical regulators of pancreatic ductal adenocarcinoma (PDAC) progression. However, their postoperative dynamics and clinical relevance remain poorly defined. In a prospective longitudinal study, blood was collected from PDAC patients prior to surgery and on postoperative day 7. Flow cytometry was used to characterize monocytes, including classical (CM), intermediate (IMM), and non-classical (NCM) subsets, along with regulatory and co-stimulatory molecules (CD71, CD40, CD141, CD80, CD86, PD-L1). Cytokine levels (IL-6, IL-10, TNF-α, IL-1β) were quantified by ELISA and correlated with clinical parameters and survival. Total monocytes and CM increased significantly at day 7, whereas IMM and NCM decreased. CD71, CD141, CD80, and CD86 expression were significantly altered across subsets, with the most pronounced reduction observed in CD86 expressing NCM. CD86 expressing NCM correlated inversely with systemic bilirubin but not CEA, lymphocytes, thrombocytes, or hospital stay. IL-6 and IL-10 increased postoperatively; IL-10 showed a tendency toward inverse correlation with CD86⁺ NCM. Low CD86 expression on NCM at day 7 was associated with reduced survival and higher relapse probability. CD86 expression on NCMs is profoundly reduced after PDAC surgery and serves as a prognostic biomarker linked to inflammation, bilirubin metabolism, survival, and recurrence. Postoperative monocyte profiling may improve risk stratification and inform early clinical decision-making.