Schlafen 4–expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia

Abstract

Chronic Helicobacter pylori infection triggers neoplastic transformation of the gastric mucosa in a small subset of patients, but the risk factors that induce progression to gastric metaplasia have not been identified. Prior to cancer development, the oxyntic gastric glands atrophy and are replaced by metaplastic cells in response to chronic gastritis. Previously, we identified schlafen 4 (Slfn4) as a GLI1 target gene and myeloid differentiation factor that correlates with spasmolytic polypeptide-expressing metaplasia (SPEM) in mice. Here, we tested the hypothesis that migration of SLFN4-expressing cells from the bone marrow to peripheral organs predicts preneoplastic changes in the gastric microenvironment. Lineage tracing in Helicobacter-infected Slfn4 reporter mice revealed that SLFN4+ cells migrated to the stomach, where they exhibited myeloid-derived suppressor cell (MDSC) markers and acquired the ability to inhibit T cell proliferation. SLFN4+ MDSCs were not observed in infected GLI1-deficient mice. Overexpression of sonic hedgehog ligand (SHH) in infected WT mice accelerated the appearance of SLFN4+ MDSCs in the gastric corpus. Similarly, in the stomachs of H. pylori-infected patients, the human SLFN4 ortholog SLFN12L colocalized to cells that expressed MDSC surface markers CD15+CD33+HLA-DRlo. Together, these results indicate that SLFN4 marks a GLI1-dependent population of MDSCs that predict a shift in the gastric mucosa to a metaplastic phenotype.

Initiation and Maintenance of Gastric Cancer: A Focus on CD44 Variant Isoforms and Cancer Stem Cells

“…A study by the Merchant laboratory identified Schlafen 4 ( Slfn4 ) as a GLI1 target gene and myeloid differentiation factor that correlated with the development of SPEM in mice 77 . A recent study by the same group then showed that migration of Slfn4-expressing cells from the bone marrow to the stomach in response to Helicobacter infection showed MDSC markers, and acquired the ability to inhibit T-cell proliferation 78 . This supports MDSC suppression of T-cell function and subsequent dampening of the immune response to create a microenvironment favoring tumor growth 79 …”

Hedgehog Signaling Modulates Interleukin‐33‐Dependent Extrahepatic Bile Duct Cell Proliferation in Mice

“…All mouse experiments were approved by the University of Michigan’s Institutional Animal Care and Use Committee. Transgenic Shh mice (promoter for cytomegalovirus [pCVM]‐ Shh ) and Gli1 lacZ/lacZ mice have been described . The Gli1 lacZ./+ and Gli1 lacZ./lacZ mice contain a knock‐in lacZ , encoding a nuclear‐localized β‐galactosidase, into exon 2 of the mouse Gli1 gene, producing a null allele .…”

“…HH signaling involves Sonic hedgehog (SHH) and Indian hedgehog (IHH) ligands, the receptor Patched‐1 (PTCH1), and their transcriptional effectors glioma‐associated oncogene 1 (GLI1), GLI2, and GLI3 . In the canonical HH pathway, cells expressing HH ligand signal to stromal cells expressing PTCH1 and GLIs in a variety of gastrointestinal tissues . In the liver, HH ligands are expressed in both epithelial cells and myofibroblasts after injury, and HH signaling is responsible for the “reactive” phenotype of injured cholangiocytes .…”

“…(1) In the canonical HH pathway, cells expressing HH ligand signal to stromal cells expressing PTCH1 and GLIs in a variety of gastrointestinal tissues. (2)(3)(4) In the liver, HH ligands are expressed in both epithelial cells and myofibroblasts after injury, and HH signaling is responsible for the "reactive" phenotype of injured cholangiocytes. (5,6) Prior studies, including from our group, suggest that HH signaling contributes to the initiation and progression of cholangiocarcinoma.…”

A Summary of the 2016 James W. Freston Conference of the American Gastroenterological Association: Intestinal Metaplasia in the Esophagus and Stomach: Origins, Differences, Similarities and Significance

“…Myeloid cell polarization into MDSCs requires hedgehog-regulated transcription factor GLI1, which induces gastric MDSCs to express Schlafen 4 , a myeloid differentiation factor. 79 Dr Merchant showed that a nucleic acid signature for MDSCs in plasma correlates with gastric metaplasia presence in both mice and humans. Collectively, her studies suggest that MDSCs are present in the gastric microenvironment before neoplastic transformation, and that they might serve as a biomarker for gastric cancer risk.…”