嗜酸性粒细胞在食管鳞状细胞癌的发展中发挥抗肿瘤作用。

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

机构信息

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.

Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

出版信息

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

DOI:10.1016/j.jcmgh.2023.08.005

PMID:37574015

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10630122/

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.

摘要

背景和目的

嗜酸性粒细胞存在于几种实体肿瘤中，其功能具有上下文依赖性。我们的目的是确定嗜酸性粒细胞在食管鳞状细胞癌（ESCC）中的作用，因为它们在 ESCC 中的作用尚不清楚。

方法

在 2 个 ESCC 队列的组织中计数嗜酸性粒细胞。用 4-NQO 处理小鼠 8 周以诱导癌前病变或 16 周以诱导癌。通过单克隆抗白细胞介素-5（IL5mAb）、重组白细胞介素-5（rIL-5）或通过缺乏嗜酸性粒细胞的（ΔdblGATA）小鼠或缺乏嗜酸性粒细胞趋化因子 eotaxin-1（Ccl11）的基因修饰来改变嗜酸性粒细胞数量。进行食管组织和嗜酸性粒细胞特异性 RNA 测序以了解嗜酸性粒细胞的功能。进行嗜酸性粒细胞与癌前或癌细胞的三维共培养，以确定嗜酸性粒细胞的直接作用。

结果

与晚期 ESCC 相比，早期 ESCC 中存在更多的活化嗜酸性粒细胞。用 4-NQO 处理的小鼠在癌前病变中表现出更多的食管嗜酸性粒细胞。相应地，上皮细胞 Ccl11 表达在具有癌前病变的小鼠中更高。使用 3 种小鼠模型（Ccl11 小鼠、ΔdblGATA 小鼠、IL5mAb 治疗）进行的嗜酸性粒细胞耗竭都显示出 4-NQO 肿瘤发生的加剧。相反，rIL-5 的治疗增加了食管嗜酸性粒细胞并预防了癌前病变和癌。组织和嗜酸性粒细胞 RNA 测序显示嗜酸性粒细胞在癌前病变中驱动氧化应激。在存在脱颗粒剂的情况下，将嗜酸性粒细胞与癌前或癌细胞进行体外共培养会导致细胞凋亡增加，而使用活性氧清除剂 NAC 则可逆转这种情况。ΔdblGATA 小鼠表现出增加的 CD4 T 细胞浸润、IL-17 和 IL-17 促肿瘤发生途径的富集。