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Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis and has been identified as a major risk factor for the development of gastric cancer (GC). Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates immune regulatory processes, including tumor-driven immune escape. Programmed death ligand 1 (PD-L1) expressed on gastric epithelium can suppress the immune system by shutting down T cell effector function. In a human cohort of subjects with gastric lesions and GC analyzed by proteomics, STAT1 increased along the cascade of progression of precancerous gastric lesions to GC and was further associated with a poor prognosis of GC (Hazard Ratio (95% confidence interval): 2.34 (1.04-5.30)). We observed that STAT1 was activated in human H. pylori -positive gastritis, while in GC, STAT1, and its target gene, PD-L1, were significantly elevated. To confirm the dependency of H. pylori , we infected gastric epithelial cells in vitro and observed strong activation of STAT1 and upregulation of PD-L1, which depended on cytokines produced by immune cells. To investigate the correlation of immune infiltration with STAT1 activation and PD-L1 expression, we employed a mouse model of H. pylori -induced gastric lesions in an Rnf43-deficient background. Here, phosphorylated STAT1 and PD-L1 were correlated with immune infiltration and proliferation. STAT1 and PD-L1 were upregulated in gastric tumor tissues compared with normal tissues and were associated with immune infiltration and poor prognosis based on the TCGA-STAD database. H. pylori -induced activation of STAT1 and PD-L1 expression may prevent immune surveillance in the gastric mucosa, allowing premalignant lesions to progress to gastric cancer.

The E3 ubiquitin ligase ring finger protein 43 (RNF43) is frequently mutated in gastric tumors and loss of RNF43 expression was suggested to be one of the key events during the transition from adenoma to gastric carcinoma. Functional studies on RNF43 have shown that it acts as a tumor suppressor by negatively regulating Wnt signaling. Interestingly, we observed that RNF43 H292R/H295R mice bearing two point mutations in the ring domain displayed thickening of the mucosa at early age but did not develop neoplasia. In this study, we infected these mice for 6 months with Helicobacter pylori , which has been described as one of the major risk factors for gastric cancer. Mice bearing mutant RNF43 H292R/H295R showed higher gastritis scores upon H. pylori infection compared to wild-type mice, accompanied by increased lymphocyte infiltration and Ifng levels. Furthermore, infected Rnf43 mutant mice developed atrophy, hyperplasia and MUC2 expressing metaplasia and displayed higher levels of the gastric stem cell marker CD44 and canonical NF-κB signaling. In summary, our results show that transactivating mutations in the tumor suppressor Rnf43 can worsen H. pylori induced pathology.