Perineural invasion reprograms the immune microenvironment through cholinergic signaling in pancreatic ductal adenocarcinoma

At the request of my authors, you must replace the abstract that is in your manuscript AND on SmartSubmit with the following version: Perineural invasion (PNI) is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of PNI on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different PNI status were compared, and the intratumoral T cell density and levels of neurotransmitters in these tissues were assessed. PNI was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe PNI. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFN-γ 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 PNI 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, PNI-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.