Gastric cancer mesenchymal stem cells derived IL-8 induces PD-L1 expression in gastric cancer cells via STAT3/mTOR-c-Myc signal axis

Li Sun,Zhihong Chen,Bo Shen,Wei Zhu,Hua Wang,Wenrong Xu,Bin Chen,Changgen Xu,Jing Xu,Miaolin Zhu,Qianqian Wang,Mei Wang,Xiangdong Zhao,Yuanyuan Zhao

doi:10.1038/s41419-018-0988-9

Abstract

The expression of PD-L1 in tumor cells is one of the main causes of tumor immune escape. However, the exact mechanism for regulating PD-L1 expression in gastric cancer (GC) cells remains unclear. Our previous studies have shown that mesenchymal stem cells (MSCs) exert broad immunosuppressive potential, modulating the activity of cells either in innate or adaptive immune system to promote tumor progress. This study aims to investigate whether GCMSCs regulate the PD-L1 expression in GC cells and explore the specific molecular mechanism. The results have shown that GCMSCs enhanced PD-L1 expression in GC cells resulting in the resistance of GC cells to CD8+ T cells cytotoxicity. However, this resistance was attenuated with IL-8 inhibition. Further studies proved that IL-8 derived from GCMSCs induced PD-L1 expression in GC cells via c-Myc regulated by STAT3 and mTOR signaling pathways. Our data indicated that blocking IL-8 derived from GCMSCs may overcome the immune escape induced by PD-L1 in GC cells and provide a potential strategy to enhance the immunotherapy efficiency in GC.

Highlights

Gastric cancer (GC) is the fourth most common malignant tumor, and the second leading cause of cancerrelated death worldwide[1]
The results have shown that GC tissues expressed higher PD-L1 than corresponding adjacent normal tissues (Fig. 1a, b), which was consistent with previous literature reports
We found that compared with bone marrow MSCs (BMMSCs)-CM, GCMSC-CM highly upregulated the expression of PD-L1 in SGC-7901 and MGC-803 (Fig. 2a, b)

Summary

Introduction

Gastric cancer (GC) is the fourth most common malignant tumor, and the second leading cause of cancerrelated death worldwide[1]. Remarkable achievements in surgical and other therapies have been obtained, there is still a poor 5-year survival rate among GC patients[2]. Immunotherapy is a major breakthrough in cancer therapy and clinical trials with PD-1/PD-L1 antibodies have shown unprecedented responses in GC. PD-L1 has been reported to be overexpressed in several malignant tumors and the mechanisms of PD-L1. Regulation was multifaceted, such as genomic aberrations, mRNA stability, transcriptional control, protein stability and oncogenic signaling[3,4]. PD-L1 expression was associated with the resistance to anticancer therapies and the poor prognosis[5,6,7].

Objectives

Methods

Results

Conclusion