Journal article
Eosinophils exert anti-tumorigenic effects in the development of esophageal squamous cell carcinoma
Cellular and molecular gastroenterology and hepatology, Vol.16(6), pp.961-983
2023
DOI: 10.1016/j.jcmgh.2023.08.005
PMCID: PMC10630122
PMID: 37574015
Abstract
Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), since their role in ESCC is unknown.
Eosinophils were enumerated in tissues from two ESCC cohorts. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks to induce pre-cancer or 16 weeks to induce carcinoma. Eosinophil number was modified by monoclonal antibody to IL-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 (Ccl11
). Esophageal tissue and eosinophil specific RNA-sequencing was performed to understand eosinophil function. 3-D co-culturing of eosinophils with pre-cancer or cancer cells was done to ascertain direct effects of eosinophils.
Activated eosinophils are present in higher numbers in early stage versus late stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in pre-cancer versus cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with pre-cancer. Eosinophil depletion using three mouse models (Ccl11
mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against pre-cancer and carcinoma. Tissue and eosinophil RNA-sequencing revealed eosinophils drive oxidative stress in pre-cancer. In vitro co-culturing of eosinophils with pre-cancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with N-acetylcysteine, a reactive oxygen species (ROS) scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 pro-tumorigenic pathways.
Eosinophils likely protect against ESCC through ROS release during degranulation and suppression of IL-17.
Details
- Title: Subtitle
- Eosinophils exert anti-tumorigenic effects in the development of esophageal squamous cell carcinoma
- Creators
- Justin JacobseZaryab Aziz - Vanderbilt University Medical CenterLili Sun - Vanderbilt University Medical CenterJasmine Chaparro - Vanderbilt University Medical CenterJennifer M Pilat - Vanderbilt University School of MedicineAaron Kwag - Vanderbilt University Medical CenterMatthew Buendia - Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Nashville, TNMae Wimbiscus - Vanderbilt University Medical CenterMotomi NasuTsuyoshi Saito - Juntendo UniversityShinji Mine - Juntendo UniversityHajime OritaFrank Revetta - Vanderbilt University Medical CenterSarah P ShortM Kay Washington - Vanderbilt University Medical CenterGirish Hiremath - Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Nashville, TNMichael K GibsonLori CoburnTatsuki Koyama - Vanderbilt University Medical CenterJeremy A GoettelChristopher S WilliamsYash A Choksi
- Resource Type
- Journal article
- Publication Details
- Cellular and molecular gastroenterology and hepatology, Vol.16(6), pp.961-983
- DOI
- 10.1016/j.jcmgh.2023.08.005
- PMID
- 37574015
- PMCID
- PMC10630122
- NLM abbreviation
- Cell Mol Gastroenterol Hepatol
- ISSN
- 2352-345X
- eISSN
- 2352-345X
- Language
- English
- Electronic publication date
- 08/11/2023
- Date published
- 2023
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984455299302771
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