Clinical significance of elevated serum soluble CD40 ligand levels as a diagnostic and prognostic tumor marker for pancreatic ductal adenocarcinoma

Abstract

BackgroundCD40-CD40 ligand (CD40L) interaction is considered to contribute to the promotion of prothrombotic responses and production of angiogenesis-associated factor in addition to adaptive immune responses. Recently, the role of soluble CD40L (sCD40L) has gained interest in cancer, although its exact functions remain unknown. This study evaluated the clinical significance of sCD40L in patients with pancreatic ductal adenocarcinoma (PDAC) and validated its utility as a PDAC diagnostic and prognostic biomarker.MethodsSerum sCD40L levels were measured by chemiluminescent immunoassay and compared among normal, chronic pancreatitis (CP, high-risk), and PDAC group in both training (n = 25 per group) and independent validation (n = 30, 30, and 55, respectively) datasets through one-way ANOVA test with the post-hoc Bonferroni method. To evaluate the diagnostic potential of serum sCD40L for PDAC, receiver operating characteristic (ROC) curves were generated and logistic regression analysis was conducted. To investigate the sCD40L-assoicated cytokines/chemokines in PDAC, cytokines/chemokines levels were analyzed by a MILLIPLEX MAP Human Cytokine/Chemokine Kit. To assess the prognostic potentials of sCD40L, Kaplan-Meier survival curve and Cox proportional-hazards regression analysis were applied.ResultsSerum sCD40L levels were significantly higher in PDAC group compared with non-cancer groups in both training (p < 0.05) and validation (p < 0.05) datasets. Clinically, serum sCD40L closely correlated with unresectability (γs = 0.342, p = 0.011) and distant metastasis (γs = 0.294, p = 0.030) of PDAC. ROC curve and logistic regression analysis demonstrated the remarkable predictive potentials of serum sCD40L for PDAC (80.0% sensitivity and 85.5% specificity at cut-off point, 0.45; logistic regression), superior to those of CA19-9 and CEA. According to cytokines/chemokines assay, serum sCD40L levels were closely correlated with serum levels of pro-angiogenic cytokines (EGF, VEGF, IL-8) and immunosuppressive cytokines (IL-6, IL-10, IL-1RA). Kaplan-Meier survival analysis demonstrated patients with high-serum sCD40L (> 35,000 ng/ml) had a poorer prognosis than those with low-serum sCD40L (log-rank, p = 0.015). Multivariate Cox regression analysis yielded a hazard ratio of 2.509 (95% CI, 1.038–6.067, p = 0.041) for mortality in the high-serum sCD40L group.ConclusionsSerum sCD40L is correlated with immunosuppression and angiogenesis in PDAC carcinogenesis/progression, and is a promising diagnostic and prognostic biomarker for PDAC superior to CA19-9 and CEA.

The prognostic value of plasma soluble CD40 ligand levels in patients with nasopharyngeal carcinoma

“…The previous report has shown that high sCD40L concentrations are associated with short survival time in patients with pancreatic ductal adenocarcinoma [32]. The current study analyzed biological and clinical variables in 312 patients with NPC, and Kaplan-Meier survival analysis and Cox proportional hazards regression models indicated that NPC patients with high plasma sCD40L concentrations had poorer prognosis than those with low plasma sCD40L concentrations.…”

“…This positive expression of CD40 is associated highly with lymphatic metastasis and tumor stage in gastric cancer patients [47]. sCD40L is produced at high concentrations in patients with pancreatic ductal adenocarcinoma, lung cancer and NPC [32][33][34]. This study found that enhanced pretreatment plasma sCD40L concentrations were correlated highly with tumor classification, lymph node classification and tumor node metastasis stage.…”

“…However, just as in the current study, a great number of researches have stored the blood samples at −70°C [23][24][25][26][27][28][29][30][31][32][33][34]. Moreover, in this study, the determination of sCD40L was tested in batches and was performed every less than 6 months.…”

“…Circulating sCD40L concentrations are increased in a great deal of human diseases such as acute coronary syndrome, severe sepsis and pancreatitis [23][24][25][26][27][28][29][30][31]. High sCD40L concentrations in peripheral blood have also been found in patients with pancreatic ductal adenocarcinoma and lung cancer [32,33]. Moreover, increased serum sCD40L concentrations are reported to be associated highly with poor survival of pancreatic ductal adenocarcinoma [32].…”

“…High sCD40L concentrations in peripheral blood have also been found in patients with pancreatic ductal adenocarcinoma and lung cancer [32,33]. Moreover, increased serum sCD40L concentrations are reported to be associated highly with poor survival of pancreatic ductal adenocarcinoma [32]. A recent research has shown that serum sCD40L concentrations are increased in patients with nasopharyngeal carcinoma (NPC) [34].…”