# Increased Herpesvirus Entry Mediator Expression on Circulating Monocytes and Subsets Predicts Poor Outcomes in Pancreatic Ductal Adenocarcinoma Patients

## TL;DR

High levels of a protein called HVEM on immune cells predict worse outcomes in pancreatic cancer patients and could help detect the disease earlier.

## Contribution

HVEM expression on monocytes is identified as a novel prognostic marker with better predictive value than CA19-9 in pancreatic ductal adenocarcinoma.

## Key findings

- HVEM expression is significantly elevated on monocytes in PDAC patients.
- Higher HVEM levels correlate with reduced survival and aggressive tumor features.
- HVEM-expressing monocytes outperform CA19-9 as a prognostic indicator.

## Abstract

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.