Abstract
The precise role of tumor associated macrophages remains unclear in pancreatic ductal adenocarcinoma (PDAC) while TGF-ß has an unclear role in metastases formation. In order to understand the role of IL23, an interleukin associated with macrophage polarization, we investigated IL23 in the context of TGF-ß expression in PDAC. We hypothesized that IL23 expression is associated with metastatic development and survival in PDAC. We investigated IL23 and TGF-ß protein expression on resected PDAC patient tumor sections who were divided into short-term (<12 months) survivors and long-term (>30 months) survivors. Panc-1 cells treated with IL23, TGF-ß, macrophages, or combinations thereof, were orthotopically implanted into NSG mice. Patients in the long-term survivor group had higher IL23 protein expression (P = 0.01). IL23 expression was linearly correlated with TGF-ß expression in patients in the short-term survivor group (P = 0.038). Macrophages induce a higher rate of PDAC metastasis in the mouse model (P = 0.02), which is abrogated by IL23 and TGF-ß treatment (P < 0.001). Macrophages serve a critical role in PDAC tumor growth and metastasis. TGF-ß contributes to a less tumorigenic TME through regulation of macrophages. Macrophages increases PDAC primary tumor growth and metastases formation while combined IL23 and TGF-ß pre-treatment diminishes these processes.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) carries one of the highest case fatality rate of any cancer and will likely become the second leading cause of cancer related death in the decade due to a rising incidence[1,2]
Seventy-five percent of the patients in the short-term survivor group had tumor lymphovascular invasion (LVI) while only 50% of patients in the long-term survivor group had tumors with LVI (P = 0.044)
We found that IL23 expression and TGF-ß expression in long-term survivors was statistically correlated (P = 0.037), suggesting a reason that each protein expression was not associated with survival in isolation
Summary
Since protein expression of IL23 and TGF-ß were significantly correlated in short term surviving patients (Fig. 2A,B), we sought to understand if there was a relationship level at the gene expression level. We found that all groups containing macrophages had significantly higher tumor burden (Fig. 4, P < 0.03) when compared to PBS control treated Panc-1 cells. By adding IL23 treatment to the Panc-1 cells treated with macrophage + TGF-ß, we found that the weight of primary tumors was less (Fig. 4B, P < 0.001) and PDAC tumor diameter was smaller (Fig. 4A, P < 0.001). In both instances, macrophages were associated with increased Panc-1 tumor growth. Macrophage co-cultured with Panc-1 cells increased primary tumor growth and metastases formation while combined IL23 and TGF-ß pre-treatment diminished these phenomena
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