Sphingosine 1 phosphate receptor-1 (S1P1) promotes tumor-associated regulatory T cell expansion: leading to poor survival in bladder cancer

Yi-Na Liu,Jia He,Han Zhang,Jiang Li,Ting-Ting Cai,Dai-Jia Huang,Xiao-Shi Zhang,Fang-Jian Zhou,Lin Zhang,Huan-He Ni

doi:10.1038/s41419-018-1298-y

Abstract

Regulatory T cells (Tregs) represent an important contributor to cancer immune escape, but the molecular mechanism responsible for Treg expansion in tumors is heterogeneous and unclear. Here, we investigated the role of S1P1, a receptor of the bioactive lipid sphingosine 1-phosphate (S1P), in regulating the crosstalk between tumor cells and tumor-associated Tregs in bladder cancer (BC). We found that the frequency of CD4+Foxp3+ Tregs was increased in circulating and tumor-infiltrating lymphocytes from BC patients. S1P1 expression was upregulated in BC tissues compared with tumor-adjacent tissues and was positively correlated with the density of tumor-infiltrated Foxp3+ Tregs. Both S1P1 and Treg predicted poor overall survival in BC patients. The in vitro data paralleled the in vivo data and suggested that the activation or overexpression of S1P1 in BC cells promoted the generation of BC-induced (i)Tregs from CD4+CD25−cells, and the generation of these cells was reversed by treatment with anti-IL-10 or anti-TGF-β. Moreover, S1P1 promoted Treg migration mediated by BC cells. Mechanistically, S1P1 activated the TGF-β signaling pathway, leading to the secretion of TGF-β and IL-10 from BC cells. In total, our findings suggest that S1P1 induces tumor-derived Treg expansion in a cell-specific manner and serves as a potent prognostic biomarker and therapeutic target in BC.

Highlights

Bladder carcinoma (BC) is the fifth most common cancer, accounting for 85–90% of primary carcinomas, and its incidence is increasing worldwide[1,2]
The S1P1 expression level and Foxp3+ Treg density were substantially increased in BC tissues compared with tumor-adjacent tissues (Fig. 1c, d, P < 0.05), and interestingly, tumor S1P1 expression was significantly correlated with the number of Foxp3+ Tregs in tumor specimens from 116 BC patients (Fig. 1e, P = 0.035, R = 0.196)
We further demonstrated that the level of S1P1 was increased in tumor tissues from BC patients with a higher frequency of tumor-infiltrating CD4+Foxp3+ Tregs than in those from BC patients with a lower frequency of tumor-infiltrating CD4+Foxp3+ Tregs (n = 3, Fig. 1f)

Summary

Introduction

Bladder carcinoma (BC) is the fifth most common cancer, accounting for 85–90% of primary carcinomas, and its incidence is increasing worldwide[1,2]. Patients with BC show evidence of acquired immune dysfunction, the expansion of regulatory T cells (Tregs)[3]. Sphingosine 1-phosphate (S1P), a potent bioactive lipid, exerts many biological effects on different types of cells, including normal cells, and these effects include changes to cell migration, proliferation, and angiogenesis[4]. There are five types of G-protein-coupled S1P receptors, and among these receptors, S1P1-3 are the most widely expressed[5]. S1P can promote the motility, survival, growth, and transformation of cancer cells through multiple pathways[6].

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Results

Conclusion