Eosinophils Exert Antitumorigenic Effects in the Development of Esophageal Squamous Cell Carcinoma

Justin Jacobse; Zaryab Aziz; Lili Sun; Jasmine Chaparro; Jennifer M Pilat; Aaron Kwag; Matthew Buendia; Mae Wimbiscus; Motomi Nasu; Tsuyoshi Saito; Shinji Mine; Hajime Orita; Frank Revetta; Sarah P Short; M Kay Washington; Girish Hiremath; Michael K Gibson; Lori A Coburn; Tatsuki Koyama; Jeremy A Goettel; Christopher S Williams; Yash A Choksi

doi:10.1016/j.jcmgh.2023.08.005

Eosinophils Exert Antitumorigenic Effects in the Development of Esophageal Squamous Cell Carcinoma

Cell Mol Gastroenterol Hepatol. 2023;16(6):961-983. doi: 10.1016/j.jcmgh.2023.08.005. Epub 2023 Aug 11.

Authors

Justin Jacobse¹, Zaryab Aziz², Lili Sun³, Jasmine Chaparro², Jennifer M Pilat⁴, Aaron Kwag², Matthew Buendia⁵, Mae Wimbiscus², Motomi Nasu⁶, Tsuyoshi Saito⁷, Shinji Mine⁸, Hajime Orita⁶, Frank Revetta⁹, Sarah P Short¹⁰, M Kay Washington⁹, Girish Hiremath⁵, Michael K Gibson¹¹, Lori A Coburn¹², Tatsuki Koyama³, Jeremy A Goettel¹³, Christopher S Williams¹⁴, Yash A Choksi¹⁵

Affiliations

¹ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, the Netherlands; Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Research and Development, Veterans Affairs Tennessee Valley Health System, Nashville, Tennessee.
² Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
³ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
⁴ Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
⁵ Division of Gastroenterology, Department of Pediatrics, Hepatology, and Nutrition, Nashville, Tennessee.
⁶ Department of Esophageal and Gastroenterological Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan; International Collaborative Research Administration, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁷ Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁸ Department of Esophageal and Gastroenterological Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁹ Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
¹⁰ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee.
¹¹ Department of Internal Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
¹² Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Research and Development, Veterans Affairs Tennessee Valley Health System, Nashville, Tennessee; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee.
¹³ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Institute for Infection Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee.
¹⁴ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Research and Development, Veterans Affairs Tennessee Valley Health System, Nashville, Tennessee; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology and Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville Tennessee.
¹⁵ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Research and Development, Veterans Affairs Tennessee Valley Health System, Nashville, Tennessee; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: yash.a.choksi@vumc.org.

Abstract

Background and aims: 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), as their role in ESCC is unknown.

Methods: Eosinophils were enumerated in tissues from 2 ESCC cohorts. Mice were treated with 4-NQO for 8 weeks to induce precancer or 16 weeks to induce carcinoma. The eosinophil number was modified by a monoclonal antibody to interleukin-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. Three-dimensional coculturing of eosinophils with precancer or cancer cells was done to ascertain direct effects of eosinophils.

Results: Activated eosinophils are present in higher numbers in early-stage vs late-stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in precancer vs cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with precancer. Eosinophil depletion using 3 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 precancer and carcinoma. Tissue and eosinophil RNA sequencing revealed eosinophils drive oxidative stress in precancer. In vitro coculturing of eosinophils with precancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with NAC, a reactive oxygen species scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 protumorigenic pathways.

Conclusion: Eosinophils likely protect against ESCC through reactive oxygen species release during degranulation and suppression of IL-17.

Keywords: Degranulation; Eosinophils; Esophageal Squamous Cell Carcinoma; Immunotherapy; Oxidative Stress.

MeSH terms

Animals
Carcinoma*
Eosinophils
Esophageal Neoplasms*
Esophageal Squamous Cell Carcinoma*
Interleukin-17
Mice
Reactive Oxygen Species

Substances

Interleukin-17
Reactive Oxygen Species

Abstract

MeSH terms

Substances

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