A circulating TH2 cytokines profile predicts survival in patients with resectable pancreatic adenocarcinoma

Abstract

Surgery is the only potentially curative option for patients with pancreatic ductal adenocarcinoma (PDAC), but metastatic relapse remains common. We hypothesized that the expression levels of inflammatory cytokines could predict recurrence of PDAC, thus allowing to select patients who most likely could benefit from surgical resection. We prospectively collected plasma at diagnosis from 287 patients with pancreatic resectable neoplasms. The expression levels of 23 cytokines were measured in 90 patients with PDAC by using a multiplex analyte profiling assay. Levels higher than cutoff identified of the T_H2 cytokines interleukin (IL)4, IL5, IL6 of macrophage inflammatory protein (MIP)1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)1, and of IL17α, IFNγ-induced protein (IP)10, and IL1b were significantly associated with a shorter median OS. In particular, levels of IL4 and IP10 higher than cutoff identified, and level of T_H1 cytokines TNFα and INFγ, and of IL9 and IL1Rα lower than cutoff identified were significantly associated with a shorter DFS. In the multivariate analysis, high IP10 was confirmed as negatively associated with OS (HR = 3.097, p = 0.014) and IL4 and TNFα remain negatively (HR = 2.75, p = 0.002) and positively (HR = 0.224, p = 0.049) associated with DFS, respectively. Simultaneous expression of low IL4 and high TNFα identified patients with best prognosis (HR = 0.313, p < 0.0001). In conclusion, we demonstrated that, among a series of cytokines, IL4 is the most significant independent prognostic factor for DFS in resectable PDAC patients, and it could be useful to select patients with high risk of early recurrence who may avoid an unnecessary resection.

Keywords: IL4; TH2 cytokines; circulating cytokine profile; pancreatic adenocarcinoma; prognostic biomarker.

Figure 1.

Strobe diagram of the study.

Figure 2.

OS and DFS of patients with PDAC stratified according to cytokines levels. Kaplan–Meier curves for OS (A) and DFS (B) by significant cytokines cutoff concentration in plasma samples. Cytokines concentration expressed as pg/mL. (C) upper left, IL4 level in patients stratified around an early relapse cutoff of 8 mo; upper right, determination of cutoff thresholds of IL4 level for PDAC patients dichotomized according to early relapse of 8 mo. All possible cutoff thresholds were considered and the corresponding odds ratios (OR) were calculated and plotted. Each data point in the line gives the corresponding OR and 95% confidence interval (dotted lines) on the y axis. Lower left, receiver operator characteristic (ROC) curves for IL4 level in patients stratified around early relapse cutoff of 8 mo; lower right, waterfall plot, green and red bars represent cases with correct or wrong classification, respectively.

Figure 3.

Combined cytokine signature predicts DFS. (A) patients were stratified for DFS on the basis of simultaneous expression of low IL4 and high TNFα. (B) tumor-immune network.