Exosomes Derived from RM-1 Cells Promote the Recruitment of MDSCs into Tumor Microenvironment by Upregulating CXCR4 via TLR2/NF-κB Pathway.

Nan Li,Haoyu Xu,Yao Zhang,Yingying Gao,Hexi Wang,Yingying Wang,Gagan Chhabra

doi:10.1155/2021/5584406

Abstract

Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor immune escape because of its remarkable immunosuppressive effect. However, the mechanism of MDSCs migrated into tumor microenvironment remains unclear. In this study, we demonstrated the recruitment of MDSCs can be promoted by exosomes derived from prostate cancer cells, which could upregulate chemokine (CXC motif) receptor 4 (CXCR4) via the TLR2/NF-κB signalling pathway. Flow cytometry detected that the percentage of MDSCs in the mice spleen and tumor tissue was significantly increased after injection with exosomes via mouse tail vein. Transwell chemotaxis assay showed the recruitment of MDSCs toward the lower chamber was enhanced after stimulation with exosomes, and the migration ability could be inhibited by AMD3100 (a CXCR4 specific inhibitor) both in vivo and in vitro. Additionally, Western blot and flow cytometry verified a remarkably increase of CXCR4 in MDSCs after incubation with exosomes; meanwhile, the protein level of TLR2 and activation of NF-κB were also strengthened obviously. Nevertheless, after blocking TLR2 by C29 (a TLR2-specific inhibitor), the expression of p-p65 and CXCR4, which were hypothesized as the downstream target of TLR2, was prominently reduced. In conclusion, prostate cancer-derived exosomes could reinforce CXCR4 expression in MDSCs through the TLR2/NF-κB signalling pathway, eventually promoting migration of MDSCs into tumor microenvironment in a CXCR4-CXCL12 axis-dependent manner.

Highlights

As one of the most prevalent cancers worldwide [1], prostate cancer (PCa) in the early stage does not emerge obvious symptoms, evolving into castration-resistant PCa (CRPC) along with local or distant metastasis [2]
En, mice were executed at the time points of 14 days, 21 days, and 28 days, respectively. e percentage of Myeloid-derived suppressor cells (MDSCs) in the spleen and tumor tissue was investigated by flow cytometry. e results showed that with the prolongation of tumor-bearing time, the percentage of MDSCs accumulated into the tumor tissue (Figures 2(a) and 2(c)) and spleen (Figures 2(b) and 2(c)) increased following the tumor growth, and the tumor growth curve has shown the positive correlation with the increasing trend of MDSCs (Figures 2(d))
Percentage of MDSCs in normal mouse spleens was set as the control group. is phenomenon might suggest that the migration of MDSCs into periphery and tumor microenvironment plays an important role in the development of tumor

Summary

Introduction

As one of the most prevalent cancers worldwide [1], prostate cancer (PCa) in the early stage does not emerge obvious symptoms, evolving into castration-resistant PCa (CRPC) along with local or distant metastasis [2]. Many studies have shown that tumor-associated immune cells are important in the development of prostate cancer [3, 4]; the mechanisms by which immunosuppression cells migrated to tumor microenvironment are still unclear. Ese diameters among 40–100 nm vesicles have been widely reported in promoting cancer development in respects of cell proliferation, migration, metastasis, angiogenesis, and chemoresistance [5, 6]. In view of their distinguished efficacy in various cancer, they were considered as vehicles of potential biomarkers in cancer diagnosis [7, 8]. MDSCs contribute to tumor development and vascularization through enhancing MMP9 and differentiating into tumor endothelial cells [16]

Methods

Results

Conclusion