Gastric cancer is the 3rd leading cause of cancer related death worldwide with only a 29% 5 year survival rate. Helicobacter pylori (H. pylori) is the major risk factor for gastric cancer and is credited for causing up to 90% of all cancers in the corpus or antrum of the stomach. H. pylori infects 4.4 billion people worldwide. Upon infection, H. pylori injects virulence factors directly into the gastric epithelium. One virulence factor, cytotoxic associated gene A (Cag A) has been highly associated with the development of gastric cancer. Cag A induces many different signaling pathways upon entering a gastric epithelial cell. One of those is the Sonic Hedgehog (SHH) signaling pathway. SHH is a gastric morphogen that is highly important for gastric development. During H. pylori infection SHH signaling recruits macrophages to the infection site. These macrophages secrete IL-1?, which inhibits acid secretion from parietal cells. This causes atrophic gastritis, the first in a few pre-neoplastic changes that occur before the development of gastric cancer. Atrophic gastritis is followed by the development of spasmolytic polypeptide/Trefoil Factor (TFF) 2-expressing metaplasia (SPEM). Following a chronic inflammatory state, SPEM cells develop into intestinal metaplasia, then dysplasia and finally gastric cancer. Unfortunately, clearance of H. pylori does not decrease the risk of developing gastric cancer once a patient has progressed to a metaplastic state. H. pylori infection also up-regulates programmed death ligand 1 (PD-L1) expression on the surface of gastric epithelial cells. PD-L1 interacts with programmed death 1 (PD-1) on the surface of cytotoxic T lymphocytes. When this interaction occurs T cells lose the ability to induce apoptosis in infected or cancer cells. PD-L1 expressing cells receive proliferative and survival signals. Here we hypothesize that PD-L1 expression induced after H. pylori infection is mediated by the SHH signaling pathway, and this PD- L1 expression is responsible for the survival of SPEM cells during chronic inflammation.
Specific Aim 1) seeks to identify the role of SHH signaling as a mediator of H. pylori-induced PD-L1 expression by using a 2D organoid system and an iPSC derived organoid system to assess the role of the SHH signaling pathway in the expression of PD-L1 following H. pylori infection.
Specific Aim 2) seeks to identify the mechanism by which SPEM cells survive chronic inflammation using a 3D organoid-immune co-culture system and a Mongolian gerbil model of gastric cancer. Mongolian gerbils will be used because mice do not develop gastric cancer following H. pylori infection. In addition, SPEM has been well characterized in Mongolian gerbils, and the subsequent markers of SPEM have been well documented. The long- term goal is to inhibit carcinogenesis in response to H. pylori infection and aid the immune response against the development of gastric cancer in high risk patients. Therefore, it is crucial to determine the signaling pathway responsible for PD-L1 expression in order to discover treatment modalities that prevent expression, thereby improving patient outcome.

Public Health Relevance

Understanding the mechanism by which H. pylori infection induces PD-L1 expression on infected gastric epithelial cells will lead to a better understanding of H. pylori pathogenesis and carcinogenesis. This research seeks to positively impact the treatment of H. pylori infected patients expressing a high risk for the development of gastric cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK120206-02
Application #
9823774
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Rivers, Robert C
Project Start
2018-09-05
Project End
2021-09-04
Budget Start
2019-09-05
Budget End
2020-09-04
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Organized Research Units
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221