Abstract 2133 Determining the impact of alternative splicing and alternative polyadenylation on Glutaminase expression in Mantle Cell Lymphoma

Helicobacter pylori (H.pylori) is a human pathogen that colonizes the stomach of more than half of the population.The infected host is unable to clear the bacteria even with the induction of innate and adaptive immune responses.Persistent H. pylori infection is the leading cause of chronic gastritis, peptic ulcer disease and gastric cancer.Virulence factors of H. pylori play an important role in the pathogenicity of H. pylori infection.The cytotoxin-associated gene A (CagA) protein of H. pylori is delivered into the host gastric epithelial cells by bacterial type IV secretion system (T4SS) and hijacks host signaling molecules to promotes neoplastic transformation of gastric epithelial cells.While the oncogenic activity of CagA is well elucidated, its potential role in immune evasion of H. pylori infection remains largely unknown.Programmed deathligand 1 (PD-L1), an immune checkpoint inhibitor, binds to its receptor PD1 on cytotoxic T cells and other immune cells, facilitating immune escape through T cell exhaustion.In this study, we found that H. pylori stimulated the expression of PD-L1 in gastric epithelial cells via activation of mammalian target of rapamycin (mTOR) in a CagA-dependent manner.mTOR is a master regulator of cell growth, proliferation, motility, survival, metabolism, and autophagy and its activation.We also found that H. pylori CagA can induced K63-linked ubiquitination of mTOR, leading to mTOR activation.The inhibition of mTOR K63-linked ubiquitination via E3 ligase inhibition decreased PD-L1 expression and the associated immune evasion.These results uncover a novel signaling cascade in which H. pylori utilizes its virulence factor to activate mTOR through K63-linked ubiquitination for the expression of PD-L1, leading to the immune evasion and persistence infection with H. pylori.