Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma

Jacobse, J.; Aziz, Z.; Sun, L.; Chaparro, J.; Pilat, J. M.; Kwag, A.; Buendia, M.; Wimbiscus, M.; Nasu, M.; Saito, T.; Mine, S.; Orita, H.; Revetta, F.; Short, S.; Washington, M. K.; Hiremath, G.; Gibson, M.; Coburn, L. A.; Koyama, T.; Goettel, J.; Williams, C.; Choksi, Y. A.

doi:10.1101/2023.06.01.543287

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bioRxiv · 10.1101/2023.06.01.543287

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma

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Abstract

Background/AimsEosinophils 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. MethodsEosinophils 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 ({Delta}dblGATA) 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. ResultsActivated 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, {Delta}dblGATA 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. {Delta}dblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 pro-tumorigenic pathways. ConclusionEosinophils likely protect against ESCC through ROS release during degranulation and suppression of IL-17.

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Jacobse, J., Aziz, Z., Sun, L., Chaparro, J., Pilat, J. M., Kwag, A., Buendia, M., Wimbiscus, M., Nasu, M., Saito, T., Mine, S., Orita, H., Revetta, F., Short, S., Washington, M. K., Hiremath, G., Gibson, M., Coburn, L. A., Koyama, T., Goettel, J., Williams, C., Choksi, Y. A.. 2023-06-05. Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma. https://doi.org/10.1101/2023.06.01.543287

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