嗜酸性粒细胞在食管鳞状细胞癌的发展过程中发挥直接和间接的抗肿瘤作用。

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

作者信息

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

出版信息

bioRxiv. 2023 Jun 5:2023.06.01.543287. doi: 10.1101/2023.06.01.543287.

DOI:10.1101/2023.06.01.543287

PMID:37333285

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10274643/

Abstract

BACKGROUND/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), since their role in ESCC is unknown.

METHODS

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 ( ). 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.

RESULTS

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 expression is higher in mice with pre-cancer. Eosinophil depletion using three mouse models ( 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. 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.

CONCLUSION

Eosinophils likely protect against ESCC through ROS release during degranulation and suppression of IL-17.

摘要

背景/目的：嗜酸性粒细胞存在于多种实体瘤中，且具有依赖环境的功能。由于嗜酸性粒细胞在食管鳞状细胞癌（ESCC）中的作用尚不清楚，我们旨在明确其在ESCC中的作用。

方法

在两个ESCC队列的组织中对嗜酸性粒细胞进行计数。用4-硝基喹啉-1-氧化物（4-NQO）处理小鼠8周以诱导癌前病变，或处理16周以诱导癌症。通过抗白细胞介素-5单克隆抗体（IL5mAb）、重组白细胞介素-5（rIL-5），或利用嗜酸性粒细胞缺陷（ΔdblGATA）小鼠或嗜酸性粒细胞趋化因子嗜酸性粒细胞趋化蛋白-1缺陷小鼠，在基因水平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，以了解嗜酸性粒细胞的功能。将嗜酸性粒细胞与癌前或癌细胞进行三维共培养，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中活化嗜酸性粒细胞数量更多。用4-NQO处理的小鼠在癌前病变阶段比癌症阶段食管嗜酸性粒细胞更多。相应地，癌前病变小鼠的上皮细胞表达更高。使用三种小鼠模型（嗜酸性粒细胞趋化蛋白-1缺陷小鼠、ΔdblGATA小鼠、IL5mAb处理）减少嗜酸性粒细胞均显示4-NQO诱导的肿瘤发生加剧。相反，用rIL-5治疗可增加食管嗜酸性粒细胞增多，并预防癌前病变和癌症。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引发氧化应激。嗜酸性粒细胞与癌前或癌细胞共培养，在存在脱颗粒剂的情况下导致细胞凋亡增加，而活性氧（ROS）清除剂N-乙酰半胱氨酸可逆转这种情况。ΔdblGATA小鼠表现出CD4 T细胞浸润增加、白细胞介素-17增加以及白细胞介素-17促肿瘤发生途径富集。