Epigenetically associated CCL20 upregulation correlates with esophageal cancer progression and immune disorder

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.