Abstract：
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Yang MW,Tao LY,Jiang YS,Yang JY,Huo YM,Liu DJ,Li J,Fu XL,He R,Lin C,Liu W,Zhang JF,Hua R,Li Q,Jiang SH,Hu LP,Tian GA,Zhang XX,Niu N,Lu P,Shi J,Xiao GG,Wang LW,Xue J,Zhang ZG,Sun YWdoi
10.1158/0008-5472.CAN-19-2689subject
Has Abstractpub_date
2020-05-15 00:00:00pages
1991-2003issue
10eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-19-2689journal_volume
80pub_type
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