嗜酸性粒细胞存在于几种实体肿瘤中，具有依赖于上下文的功能。我们的目标是定义嗜酸性粒细胞在食管鳞状细胞癌（ESCC）中的贡献，因为它们在ESCC中的作用尚不清楚。我们对两个ESCC队列的组织进行了嗜酸性粒细胞计数。小鼠在接受4-硝基喹啉-1-酮（4-NQO）处理8周或16周后诱导出癌前病变或癌症。通过抗白细胞介素-5（IL5mAb）单克隆抗体、重组白细胞介素-5（rIL-5）或基因上缺乏嗜酸性粒细胞（ΔdblGATA）小鼠或缺乏嗜酸性粒细胞趋化因子嗜酸性蛋白-1（Ccl11-/-）的小鼠改变嗜酸性粒细胞数量。对食管组织和嗜酸性粒细胞特异性RNA测序进行了研究以了解嗜酸性粒细胞的功能。进行了嗜酸性粒细胞与癌前病变或肿瘤细胞的三维共培养，以确定嗜酸性粒细胞的直接效应。 在早期和晚期ESCC中，激活的嗜酸性粒细胞数量较多。接受4-NQO处理的小鼠在癌前病变中具有更多的食管嗜酸性粒细胞，而在癌症中则较少。相应地，具有癌前病变的小鼠的上皮细胞Ccl11表达较高。使用三种小鼠模型（Ccl11-/-小鼠、ΔdblGATA小鼠、IL5mAb治疗）消耗嗜酸性粒细胞均导致4-NQO肿瘤发生加重。相反，rIL-5的治疗增加了食管嗜酸性粒细胞，并对癌前病变和癌症提供了保护。组织和嗜酸性粒细胞RNA测序揭示嗜酸性粒细胞在癌前病变中驱动氧化应激。体外嗜酸性粒细胞与癌前病变或肿瘤细胞的共培养导致在去颗粒化剂存在时的细胞凋亡增加，该效应可通过反应性氧化物清除剂N-乙酰半胱氨酸逆转。ΔdblGATA小鼠表现出增加的CD4T细胞浸润，IL-17的富集以及IL-17促肿瘤通路的富集。 嗜酸性粒细胞可能通过去颗粒化后释放的活性氧化物对抗ESCC，并抑制IL-17。 版权所有© 2023 The Authors。由Elsevier Inc.发表，保留所有权利。

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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.