Li Nan, Wang Yingying, Xu Haoyu, Wang Hexi, Gao Yingying, Zhang Yao
Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 402160, China.
Chongqing University Cancer Hospital, Chongqing 400030, China.
J Oncol. 2021 Oct 8;2021:5584406. doi: 10.1155/2021/5584406. eCollection 2021.
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-B 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-B 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-B signalling pathway, eventually promoting migration of MDSCs into tumor microenvironment in a CXCR4-CXCL12 axis-dependent manner.
髓源性抑制细胞（MDSCs）因其显著的免疫抑制作用在肿瘤免疫逃逸中发挥关键作用。然而，MDSCs迁移至肿瘤微环境的机制仍不清楚。在本研究中，我们证明前列腺癌细胞来源的外泌体可促进MDSCs的募集，其可通过Toll样受体2（TLR2）/核因子κB（NF-κB）信号通路上调趋化因子（CXC基序）受体4（CXCR4）。流式细胞术检测发现，经小鼠尾静脉注射外泌体后，小鼠脾脏和肿瘤组织中MDSCs的百分比显著增加。Transwell趋化实验表明，用外泌体刺激后，MDSCs向下室的募集增强，且在体内和体外，AMD3100（一种CXCR4特异性抑制剂）均可抑制其迁移能力。此外，蛋白质印迹法和流式细胞术证实，与外泌体共孵育后，MDSCs中CXCR4显著增加；同时，TLR2蛋白水平和NF-κB的激活也明显增强。然而，用C29（一种TLR2特异性抑制剂）阻断TLR2后，作为TLR2下游靶点的磷酸化p65和CXCR4的表达显著降低。总之，前列腺癌来源的外泌体可通过TLR2/NF-κB信号通路增强MDSCs中CXCR4的表达，最终以CXCR4-CXCL12轴依赖的方式促进MDSCs迁移至肿瘤微环境。
