Helicobacter pylori Infection of the Gastric Epithelium Promotes Programmed Death Ligand 1 Expression and the Formation of Premalignant Lesions

Abstract

BackgroundHelicobacter pylori (H. pylori) is the number one risk factor for gastric cancer. Currently the 5‐year‐survival rate for gastric cancer is only 29%. Our laboratory has reported that H. pylori infection results in the up‐regulation of the Sonic Hedgehog (SHH) signaling pathway mediated by an increase in the transcriptional activity of NF‐kB. In addition, H. pylori infection induces the expression of programmed death ligand 1 (PD‐L1) on gastric epithelial cells. This expression inhibits T cell proliferation and effector function.HypothesisH. pylori‐induced PD‐L1 expression on the surface of gastric epithelial cells is mediated by the SHH signaling pathway.MethodsHuman‐derived gastric organoids (huFGOs) were generated from sleeve gastrectomies. These huFGOs were then transferred to a collagen‐coated transwell where they readily formed a 2D gastric epithelial cell monolayer (huGEM). The huGEM culture was apically treated with H. pylori. A second experimental group was also infected with H. pylori, but was treated with Vismodegib, a smoothened inhibitor. Gli2 and PD‐L1 expression was analyzed by qRT‐PCR and immunofluorescence. A chromatin immunoprecipitation (ChIP) assay was used to analyze Gli2 binding to the PD‐L1 promoter region. Gli3 was used as a positive control.Results1) HuGEM cultures infected with H. pylori express significantly more PD‐L1: H. pylori infection significantly increased PD‐L1 expression in huGEM cultures 48 hours post‐infection, when compared to uninfected monolayers. This response was blocked by pretreatment with Hedgehog inhibitor vismodegib. 2) Transcriptionally active Gli2 promotes PD‐L1 expression in H. pylori infected huGEM cultures: Transcriptionally active Gli2 was bound to the zinc finger motif of the promoter region of PD‐L1 upon the infection of gastric epithelial monolayers in response to H. pylori infection.ConclusionH. pylori‐induced PD‐L1 expression is mediated by the SHH signaling pathway within the gastric epithelium. Cells infected with H. pylori that express PD‐L1 may freely gain mutations while being protected from the immune response, creating premalignant lesions progressing to gastric cancer.Support or Funding InformationSteven Goldman Memorial Pancreatic Cancer Research Grant (Zavros) 1RO1DK083402This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.