Induction of Th17 Cells in the Tumor Microenvironment Improves Survival in a Murine Model of Pancreatic Cancer

Abstract

An important mechanism by which pancreatic cancer avoids anti-tumor immunity is by recruiting regulatory T cells (Treg) to the tumor microenvironment. Recent studies suggest that suppressor Treg and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Since IL-6 in the presence of TGF-β has been shown to inhibit Treg development and induce Th17 cells, we hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression. Pan02 murine pancreatic tumor cells that secrete TGF-β were transduced with the gene encoding IL-6. C57BL/6 mice were injected subcutaneously with wildtype (WT Pan02), empty vector (EV Pan02), or IL-6 transduced Pan02 cells (IL-6 Pan02) to investigate the impact of IL-6 secretion in the tumor microenvironment. Mice bearing IL-6 Pan02 tumors demonstrated significant delay in tumor growth and better overall median survival compared with mice bearing WT or EV Pan02 tumors. Immunohistochemical analysis demonstrated an increase in Th17 cells (CD4+IL-23R+ cells and CD4+IL-17+ cells) in tumors of the IL-6 Pan02 group compared with WT or EV Pan02 tumors. The upregulation of IL-17-secreting CD4+ tumor-infiltrating lymphocytes was substantiated at the cellular level by flow cytometry and ELISPOT assay, and mRNA level for RORγt and IL-23 receptor by RT-PCR. Thus, the addition of IL-6 to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer. The delayed tumor growth and improved survival suggests that induction of Th17 in the tumor microenvironment produces an anti-tumor effect.

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

“…Th1 and Th17 cells have been reported to display antitumor activity and regulate tumor growth. [48][49][50][51] The effect on NK cell depletion on CD4…”

Vaccination With ENO1 DNA Prolongs Survival of Genetically Engineered Mice With Pancreatic Cancer

“…The massive secretion of IL-6 in the pancreas of ENO1-vaccinated mice (data not shown) may explain the increase of Th17 rather than FoxP3 ϩ cells. 24 Th17 cells recruit neutrophils and eosinophils, 25 also present in pancreatic tumor lesions from empty-vaccinated mice (data not shown), and this native immune response partly impeded tumor progression, particularly at the beginning; indeed, at 24 weeks of age, both empty-and ENO1-vaccinated mice presented a lower percentage of transformed pancreatic ducts compared with untreated mice. However, only the combination of the innate and acquired immune responses induced by ENO1 vaccination was able to significantly delay tumor progression.…”

Gut Flora: In the Treatment of Disease

“…Mice experimentally colonized with Helicobacter hepaticus and enterotoxigenic Bacteroides fragilis exhibit colonic Th17 inflammatory infiltrates that appear to have a beneficial role in human ovarian cancer [9], murine melanoma, pancreatic and colon cancer [10][11][12]. It has also been found that Helicobacter pylori can alter stomach pH and acid reflux, which could protect against Barrett's esophagus and esophageal cancer [13].…”