Search

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8 + T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8 + T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8 + T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8 + T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8 + T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion., (©2020 American Association for Cancer Research.)

Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell-related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1 hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1 hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1. Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293-305. ©2018 AACR ., (©2018 American Association for Cancer Research.)