# MDSC Polarization and Helicobacter-induced Gastric Metaplasia

> **NIH NIH R56** · UNIVERSITY OF ARIZONA · 2022 · $409,682

## Abstract

Metaplastic changes in the stomach typically develop when the gastric epithelium responds to chronic
inflammation induced by such organisms as Helicobacter pylori (H. pylori). We previously showed that a subset
of interferon (IFN)-regulated myeloid cells express Schlafen4 (Slfn4), a direct target of the Gli1 transcription
factor and exhibit T cell suppressor function indicative of myeloid-derived suppressor cells (MDSCs). These
granulocytic myeloid-derived suppressor cell subset (Gr-MDSCs) contribute to the emergence of gastric
intestinal metaplasia and spasmolytic-polypeptide-expressing metaplasia (SPEM). We propose that debris
from damaged gastric epithelia and immune cells as well as dying bacteria induce a signal transduction
pathway generate pathogen recognition ligands collectively known as damage-activated molecular patterns or
DAMPs. Type 1 interferons (IFNs) are typically induced by DAMP ligands, e.g., HMGB1, mitochondrial and
unmethylated CpG DNA. We have recently found that a SNP within the human TLR9 promoter correlates with
atrophy, IM, and GAC. Moreover, the TLR9 SNP creates an NFB binding site resulting in higher TLR9
expression. H. pylori infection sensed by both plasmacytoid dendritic cells (pDC) and gastric epithelial cells
(GEC) induces TLR9 expression and ultimately secrete type 1 IFNs (IFNα/β). Thus, in addition to host
signaling from injection of the H. pylori virulence factor CagA, H. pylori remnants and cell debris are capable of
initiating an immune suppressor response. Since we previously showed that the presence of these Slfn4+-
MDSCs correlates with early pre-neoplastic changes, we hypothesize that crosstalk between a subset of
immune suppressor cells (SLFN+-MDSCs) and gastric epithelial cells stimulate feedforward signals that
ultimately re-program the epithelium towards metaplasia, before the appearance of gastric cancer. Hedgehog
signaling (Gli1) and IFNα synergistically induce Slfn4+/SLFN12L+-MDSCs. Three Specific aims are proposed:
In Aim 1, we will determine the impact of DAMP ligands (H. pylori DNA) on IFN-producing pDCs versus
gastric epithelial cells. In Aim 2, we will demonstrate how Schlafens protect a subset of MDSCs from self-
destruction by IFN-induced ROS. In Aim 3, we will demonstrate how PDE inhibition blocks Slfn4/SLFN12L+-
MDSCs and modulates the immune microenvironment in an autochthonous model of gastric tumorigenesis. A
combination of mouse models and human organoids will be used to understand the role of DAMP ligands in
shaping the immune microenvironment after chronic inflammation has occurred. Conditional deletion of Slfn4
and knockdown of the human ortholog SLFN12L will be used to dissect how these Schlafens protect the IFN-
responsive MDSCs from cell death. Finally, since modulating the immune microenvironment plays a significant
role in tumor growth, we will examine whether small molecules that disrupt or eliminate these Slfn4/SLFN12L
impact tumor growth. Completion of these aims will resu...

## Key facts

- **NIH application ID:** 10687293
- **Project number:** 2R56DK118563-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** JUANITA L. MERCHANT
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,682
- **Award type:** 2
- **Project period:** 2018-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10687293

## Citation

> US National Institutes of Health, RePORTER application 10687293, MDSC Polarization and Helicobacter-induced Gastric Metaplasia (2R56DK118563-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10687293. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*