L1CAM Overexpression Promotes Tumor Progression Through Recruitment of Regulatory T Cells in Esophageal Carcinoma

L1 cell adhesion molecule (L1CAM) exhibits an oncogenic function in tumor. However, the link between L1CAM and tumor microenvironment is still obscure in esophageal squamous cell carcinoma (ESCC) patients. In this study, we investigated how L1CAM expression by ESCC affects the characteristics of tumor cells and the tumor microenvironment. Here, we found that L1CAM expression is significantly elevated in ESCC tissues and correlated with worse prognosis.Ablation of L1CAM in ESCC cells inhibited tumor growth and migration, whereas increased tumor cell apoptosis. In the tumor microenvironment, L1CAM was correlated with regulatory T cells (Tregs) infiltration in ESCC through affecting CCL22 secretion. Mechanistically, L1CAM facilitated CCL22 expression through activating PI3K/Akt/NF-κB signaling pathway, and furthermore CCL22 recruited Tregs into tumor site, Tregs secreted TGF-β to promote L1CAM expression via Smad2/3 in a positive feedback loop.  Collectively, our findings provide new insight into the mechanism of immune evasion mediated by L1CAM, suggesting that targeting L1CAM-CCL22-TGF-β crosstalk between tumor cells and Tregs could offer a unique locus to improve the treatment of patients in ESCC. Funding Statement: This study was supported by grants from the State's Key Project of Research and Development Plan [No. 2016YFC1303501], National Natural Science Foundation of China [No. 81802857 and No. 81702810]. Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: All the patients signed the informed consent before collected tissues or associated clinical information, and this research was approved by the Institutional Ethical Committee of the First Affiliated Hospital of Zhengzhou University.