Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
Department of Immunology, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
Pathol Res Pract. 2021 Dec;228:153683. doi: 10.1016/j.prp.2021.153683. Epub 2021 Nov 9.
Chemokines have distinct effects on tumor progression by affecting cancer immunity and tumorigenesis. However, the characteristic chemokine profiles and their roles in immune cell recruitment and cancer cell biology are not entirely understood in esophageal cancer. Here, we scrutinized chemokine's expression profiles in independent esophageal cancer cohorts and identified the elevated CCL20 as a risk factor to predict patients' prognosis regardless of histology subtypes. Enhanced CCL20 expression was also associated with the acquisition of metastatic potential. Mechanistically, the upregulation of CCL20 in tumor cells was associated with promoter hypomethylation. Furthermore, by analyzing single-cell RNA sequencing data of a mouse model mimicking human ESCC development, we observed an imbalance among CD4 T subtypes in the tumor microenvironment, namely Ccr6 Th17 and Treg cells infiltration alongside the elevated Ccl20 expression in abnormal epithelial cells during the tumorigenic process. Together, these results reveal that hypomethylation-induced CCL20 promotes esophageal cancer progression and immune disorder. Targeting CCL20 might be a promising therapeutic approach in esophageal cancer.
趋化因子通过影响癌症免疫和肿瘤发生对肿瘤进展具有明显的影响。然而，在食管癌中，趋化因子的特征谱及其在免疫细胞募集和癌细胞生物学中的作用尚不完全清楚。在这里，我们在独立的食管癌队列中仔细研究了趋化因子的表达谱，并确定了升高的 CCL20 是一个风险因素，可以预测患者的预后，而与组织学亚型无关。增强的 CCL20 表达也与获得转移潜能有关。从机制上讲，肿瘤细胞中 CCL20 的上调与启动子低甲基化有关。此外，通过分析模拟人类 ESCC 发展的小鼠模型的单细胞 RNA 测序数据，我们观察到肿瘤微环境中 CD4 T 亚型之间的失衡，即在肿瘤发生过程中，异常上皮细胞中 Ccr6 Th17 和 Treg 细胞浸润以及 Ccl20 表达升高。总之，这些结果表明，低甲基化诱导的 CCL20 促进了食管癌的进展和免疫紊乱。靶向 CCL20 可能是治疗食管癌的一种有前途的方法。
