The Microarchitecture of Pancreatic Cancer as Measured by Diffusion-Weighted Magnetic Resonance Imaging Is Altered by T Cells with a Tumor Promoting Th17 Phenotype.

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a diagnostic tool that is increasingly used for the detection and characterization of focal masses in the abdomen, among these, pancreatic ductal adenocarcinoma (PDAC). DW-MRI reflects the microarchitecture of the tissue, and changes in diffusion, which are reflected by changes in the apparent diffusion coefficient (ADC), are mainly attributed to variations in cellular density, glandular formation, and fibrosis. When analyzing the T cell infiltrates, we found an association of a tumor-promoting subpopulation, characterized by the expression of interleukin (IL) 21 and IL26, with high ADC values. Moreover, the presence of IL21+ and IL26+ positive T cells was associated with poor prognosis. Pancreatic cancers-but not healthy pancreatic tissue-expressed receptors for IL21 and IL26, a finding that could be confirmed in pancreatic cell lines. The functionality of these receptors was demonstrated in pancreatic tumor cell lines, which showed phosphorylation of ERK1/2 and STAT3 pathways in response to the respective recombinant interleukins. Moreover, in vitro data showed an increased colony formation of tumor cells. In summary, our data showed an association of IL21+ and IL26+ immune cell infiltration, increased ADC, and aggressive tumor disease, most likely due to the activation of the key cancer signaling pathways ERK1/2 and STAT3 and formation of tumor colonies.

Interleukin 21 Receptor/Ligand Interaction Is Linked to Disease Progression in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) displays a marked fibro-inflammatory microenvironment in which infiltrated immune cells fail to eliminate the tumor cells and often-rather paradoxically-promote tumor progression. Of special interest are tumor-promoting T cells that assume a Th17-like phenotype because their presence in PDAC tissue is associated with a poor prognosis. In that context, the role of IL-21, a major cytokine released by Th17-like cells, was assessed. In all tissue samples (n = 264) IL-21+ immune cells were detected by immunohistochemistry and high density of those cells was associated with poor prognosis. In the majority of patients (221/264), tumor cells expressed the receptor for IL-21 (IL-21R) and also a downstream target of IL-21, Blimp-1 (199/264). Blimp-1 expression closely correlated with IL-21R expression and multivariate analysis revealed that expression of both IL-21R and Blimp-1 was associated with shorter survival time of the patients. In vitro data using pancreatic tumor cells lines provided a possible explanation: IL-21 activated ERK and STAT3 pathways and upregulated Blimp-1. Moreover, IL-21 increased invasion of tumor cell lines in a Blimp-1-dependent manner. As an in vivo correlate, an avian xenograft model was used. Here again Blimp-1 expression was significantly upregulated in IL-21 stimulated tumor cells. In summary, our data showed an association of IL-21+ immune cell infiltration and IL-21 receptor expression in PDAC with poor survival, most likely due to an IL-21-mediated promotion of tumor cell invasion and enhanced colony formation, supporting the notion of the tumor-promoting abilities of the tumor microenvironment.