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

Nan Li; Yingying Wang; Haoyu Xu; Hexi Wang; Yingying Gao; Yao Zhang

doi:10.1155/2021/5584406

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

J Oncol. 2021 Oct 8:2021:5584406. doi: 10.1155/2021/5584406. eCollection 2021.

Authors

Nan Li^{1

2}, Yingying Wang³, Haoyu Xu¹, Hexi Wang¹, Yingying Gao⁴, Yao Zhang¹

Affiliations

¹ Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 402160, China.
² Chongqing University Cancer Hospital, Chongqing 400030, China.
³ Department of Oncology, People Hospital of Jiulongpo District, Chongqing 400050, China.
⁴ Department of Laboratory Diagnosis, People's Hospital of Banan District, Chongqing 401300, China.

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.