Department of Laboratory Diagnosis, Chongqing Medical University, Chongqing, 408000, China.
Department of Laboratory Diagnosis, Jiamusi University, Jiamusi, 154000, Heilongjiang, China.
Cell Commun Signal. 2020 Jul 8;18(1):106. doi: 10.1186/s12964-020-00611-z.
Although Myeloid-derived suppressor cells (MDSCs) have a prominent ability to suppress the immune responses of T lymphocytes and propel tumor immune escape, a lack of profound systemic immunesuppression in tumor-bearing mice and tumor patients. The underlying mechanism of these remains unclear.
For this purpose, renal cancer-derived exosomes (RDEs) were first labeled with PKH67 and been observed the internalization by MDSCs. Flow cytometry analysis showed the proportion and activity change of MDSCs in spleen and bone marrow induced by RDEs. Further, western blot experiments were used to verify triggered mechanism of MDSCs by RDEs. Finally, proliferation and cytotoxicity of cytotoxic T lymphocytes (CTLs) co-cultured with MDSCs in vitro and a series of experiments in vivo were performed to demonstrate the specific inhibitory effect of RDEs-induced MDSCs.
This study suggested that RDEs crucially contributed to presenting antigenic information, activating and driving specific immunosuppressive effect to MDSCs. HSP70, which is highly expressed in RDEs, initiate this process in a toll like receptor 2 (TLR2)-dependent manner. Importantly, RDEs-induced MDSCs could exert an antigen-specific immunosuppression effect on CTL and specific promote renal tumors-growth and immune escape in consequence.
The immunosuppression mediated by MDSCs which is induced by RDEs is antigen-specific. HSP70, which is highly expressed in RDEs, plays a pivotal role in this process. Targeted abrogating the function of MDSCs, or eliminating the expression of HSP70 in exosomes, or blocking the crosstalk between them provides a new direction and theoretical support for future immunotherapy. Video abstract.
髓源抑制细胞（MDSCs）具有显著抑制 T 淋巴细胞免疫反应并促进肿瘤免疫逃逸的能力，但荷瘤小鼠和肿瘤患者缺乏深刻的系统性免疫抑制。其潜在机制尚不清楚。
为此，首先用 PKH67 标记肾癌细胞衍生的外泌体（RDEs），观察 MDSCs 的内化情况。流式细胞术分析显示 RDEs 诱导脾和骨髓中 MDSCs 的比例和活性变化。进一步，采用 Western blot 实验验证 RDEs 触发 MDSCs 的机制。最后，进行体外共培养 MDSCs 与细胞毒性 T 淋巴细胞（CTLs）的增殖和细胞毒性实验以及一系列体内实验，证明 RDEs 诱导的 MDSCs 具有特异性抑制作用。
本研究表明，RDEs 对呈递抗原信息、激活和驱动 MDSCs 的特异性免疫抑制作用至关重要。高度表达于 RDEs 的热休克蛋白 70（HSP70）以 Toll 样受体 2（TLR2）依赖性方式启动这一过程。重要的是，RDEs 诱导的 MDSCs 可对 CTL 发挥抗原特异性免疫抑制作用，并特异性促进肾肿瘤的生长和免疫逃逸。
RDEs 诱导的 MDSCs 介导的免疫抑制作用是抗原特异性的。高度表达于 RDEs 的热休克蛋白 70（HSP70）在这一过程中发挥关键作用。靶向阻断 MDSCs 的功能，或消除外泌体中 HSP70 的表达，或阻断它们之间的相互作用，为未来的免疫治疗提供了新的方向和理论支持。
