A circulating T_H2 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 TH2 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 TH1 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.

Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3

“…helper T lymphocytes (CD3 + CD4 + cells), regulatory T lymphocytes (CD3 + CD4 + CD25 + FoxP3 + cells, Tregs), B lymphocytes (CD3 − CD19 + cells), regulatory B cells (CD3 − CD19 + CD25 + FoxP3 + cells, Bregs), myeloid-dendritic cells (CD11b + CD11c + HLA-DR + cells, DCs), plasmacitoid DCs (CD11b + CD11c − CD123 + , pDCs), macrophages (CD 14 + HLA-DR + CD68 + CD206 + cells), granulocytes (PMNs, CD14 − CD15 + CD11b + cells) as well as two MDSC subsets: e-MDSCs (Lin − HLA-DR − CD11b + CD33 + cells) and M-MDSCs (CD14 + HLA-DR −/lo cells) (Additional file 1: Figure S1). Notably, we found that PDAC tissues have a higher CD45 + cell infiltrate than their normal counterpart, likely reflecting the ability of the tumor or surrounding stroma to release soluble factors attracting immune cells [20,21] (Fig. 1b), supporting the concept that PDAC is a tumor with an immune-hostile tumor microenvironment [24].…”

Plasma IL8 Is a Biomarker for TAK1 Activation and Predicts Resistance to Nanoliposomal Irinotecan in Patients with Gemcitabine-Refractory Pancreatic Cancer

“…including healthy volunteers and patients with pancreatic cancer with resectable, locally advanced or metastatic disease, IL8 levels were higher in patients with cancer than in healthy controls but were not associated with survival differences (35). More recently, we conducted the most comprehensive profiling of cytokines in the largest prospective cohort of patients with resectable pancreatic cancer to date and IL8 had no prognostic value in this cohort of patients (36). Excluded a prognostic role for IL8, we acknowledge that its negative predictive value could be although extended also to other cytotoxic agents different from nal-IRI that induce in pancreatic cancer cells a proapoptotic stimuli by which a TAK1 activation mirrored by IL8 could protect.…”

Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers

“…T h 2 lymphocytes help B cells produce antibodies and suppress the action of cytotoxic T cells [16]. Intriguingly, a low circulating level of IL-4 can identify resectable pancreatic adenocarcinoma patients with better prognosis [32].…”