MDSC Polarization and Helicobacter-induced Gastric Metaplasia

胃的化生改变通常发生在胃上皮对慢性肿瘤有反应的时候

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 result in a better understanding of the how this important subset of immune modulatory cells are induced, maintained and ultimately targeted by small molecules.