Human Gastric Cancer Mesenchymal Stem Cell-Derived IL15 Contributes to Tumor Cell Epithelial-Mesenchymal Transition via Upregulation Tregs Ratio and PD-1 Expression in CD4+T Cell

Abstract

Several studies show that mesenchymal stem cells (MSCs) homing to tumors not only provide the microenvironment for tumor cells but also promote tumor growth and metastasis. However, the exact mechanism remains unclear. Our study aims to investigate the role of gastric cancer MSCs (GCMSCs)-derived IL15 during GC progression. The effects of IL15 secreted by GCMSCs on GC development were evaluated by detecting the stemness, epithelial-mesenchymal transition (EMT), and migration abilities of GC cell lines. The expression of IL15 in serum and tissues of GC patients was also assessed. We found that IL15 derived from GCMSCs enhanced stemness, induced EMT and promoted migration of GC cell lines. The level of IL15 was higher in GC patients both in serum and tissues compared with that in healthy donors, which was associated with lymph node metastasis. In addition, the results have shown that IL15 in GC microenvironment was mainly produced by GCMSCs. Moreover, IL15 upregulated Tregs ratio through activation of STAT5 in CD4⁺T cells was accompanied by elevated expression of programmed cell death protein-1 (PD-1). Our data proved that the high concentration of IL15 in tumor microenvironment, which was mainly secreted by GCMSCs, may contribute to tumor cell metastasis and offer a new opportunity to develop effective therapeutics for intercepting tumor progression.

Keywords: IL15; PD-1; Treg; gastric cancer; mesenchymal stem cell; metastasis.