L1CAM overexpression promotes tumor progression through recruitment of regulatory T cells in esophageal carcinoma

Xuan Zhao; Shasha Liu; Xinfeng Chen; Jianyi Zhao; Feng Li; Qitai Zhao; Tan Xie; Lan Huang; Zhen Zhang; Yu Qi; Yang Yang; Song Zhao; Yi Zhang

doi:10.20892/j.issn.2095-3941.2020.0182

L1CAM overexpression promotes tumor progression through recruitment of regulatory T cells in esophageal carcinoma

Cancer Biol Med. 2021 Mar 12;18(2):547-561. doi: 10.20892/j.issn.2095-3941.2020.0182. Online ahead of print.

Authors

Xuan Zhao^{1

2}, Shasha Liu^{1

2}, Xinfeng Chen^{1

2}, Jianyi Zhao³, Feng Li^{1

2}, Qitai Zhao^{1

2}, Tan Xie⁴, Lan Huang^{1

2}, Zhen Zhang^{1

2}, Yu Qi³, Yang Yang³, Song Zhao³, Yi Zhang^{1

2

5

6}

Affiliations

¹ Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
² Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
³ Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
⁴ Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
⁵ School of Life Sciences, Zhengzhou University, Zhengzhou 450052, China.
⁶ Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou 450052, China.

PMID: 33710805
PMCID: PMC8185865
DOI: 10.20892/j.issn.2095-3941.2020.0182

Abstract

Objective: L1 cell adhesion molecule (L1CAM) exhibits oncogenic activity in tumors. However, the link between L1CAM and the tumor microenvironment remains poorly understood in patients with esophageal squamous cell carcinoma (ESCC). In this study, we investigated how L1CAM expression in ESCC affects the oncogenic characteristics of tumor cells and the tumor microenvironment.

Methods: Human ESCC samples were collected, and the mRNA and protein levels of L1CAM were examined by real-time PCR and immunohistochemistry. Overexpression and knockdown gene expression assays were used for mechanistic studies. The cell proliferation and cell cycle were measured with CCK-8 assays and flow cytometry. Cell migration and invasion ability were measured with Transwell assays. Multiplex bead-based assays were performed to identity the factors downstream of L1CAM. Xenograft studies were performed in nude mice to evaluate the effects of L1CAM on tumor growth and regulatory T cell (Treg) recruitment.

Results: L1CAM expression was significantly elevated in ESCC tissues (P < 0.001) and correlated with poorer prognosis (P < 0.05). Ablation of L1CAM in ESCC cells inhibited tumor growth and migration, and increased tumor cell apoptosis (P < 0.05). In the tumor microenvironment, L1CAM expression correlated with Treg infiltration in ESCC by affecting CCL22 secretion. Mechanistically, L1CAM facilitated CCL22 expression by activating the PI3K/Akt/NF-κB signaling pathway. Furthermore, CCL22 promoted Treg recruitment to the tumor site; the Tregs then secreted TGF-β, which in turn promoted L1CAM expression via Smad2/3 in a positive feedback loop.

Conclusions: 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 may offer a unique means to improve treatment of patients with ESCC.

Keywords: CCL22; L1CAM; TGF-β; Tregs; esophageal squamous cell carcinoma.

Abstract

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