Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China.
Clin Exp Immunol. 2021 Jul;205(1):53-62. doi: 10.1111/cei.13594. Epub 2021 May 7.
High expression of the inhibitory receptor programmed cell death ligand 1 (PD-L1) on tumor cells and tumor stromal cells have been found to play a key role in tumor immune evasion in several human malignancies. However, the expression of PD-L1 on bone marrow mesenchymal stem cells (BMSCs) and whether the programmed cell death 1 (PD-1)/PD-L1 signal pathway is involved in the BMSCs versus T cell immune response in multiple myeloma (MM) remains poorly defined. In this study, we explored the expression of PD-L1 on BMSCs from newly diagnosed MM (NDMM) patients and the role of PD-1/PD-L1 pathway in BMSC-mediated regulation of CD8 T cells. The data showed that the expression of PD-L1 on BMSCs in NDMM patients was significantly increased compared to that in normal controls (NC) (18·81 ± 1·61 versus 2·78± 0·70%; P < 0·001). Furthermore, the PD-1 expression on CD8 T cells with NDMM patients was significantly higher than that in normal controls (43·22 ± 2·98 versus 20·71 ± 1·08%; P < 0·001). However, there was no significant difference in PD-1 expression of CD4 T cells and natural killer (NK) cells between the NDMM and NC groups. Additionally, the co-culture assays revealed that BMSCs significantly suppressed CD8 T cell function. However, the PD-L1 inhibitor effectively reversed BMSC-mediated suppression in CD8 T cells. We also found that the combination of PD-L1 inhibitor and pomalidomide can further enhance the killing effect of CD8 T cells on MM cells. In summary, our findings demonstrated that BMSCs in patients with MM may induce apoptosis of CD8 T cells through the PD-1/PD-L1 axis and inhibit the release of perforin and granzyme B from CD8 T cells to promote the immune escape of MM.
高表达的抑制性受体程序性细胞死亡配体 1（PD-L1）在肿瘤细胞和肿瘤基质细胞上，已被发现对几种人类恶性肿瘤的肿瘤免疫逃逸起关键作用。然而，骨髓间充质干细胞（BMSCs）上 PD-L1 的表达情况，以及 PD-1/PD-L1 信号通路是否参与多发性骨髓瘤（MM）中的 BMSCs 与 T 细胞免疫反应，仍未得到明确界定。在这项研究中，我们探索了新诊断的 MM（NDMM）患者的 BMSCs 上 PD-L1 的表达情况，以及 PD-1/PD-L1 通路在 BMSC 介导的 CD8 T 细胞调节中的作用。数据表明，与正常对照（NC）相比，NDMM 患者的 BMSCs 上 PD-L1 的表达显著增加（18·81 ± 1·61 对 2·78± 0·70%；P < 0·001）。此外，与 NC 相比，NDMM 患者的 CD8 T 细胞上 PD-1 的表达显著更高（43·22 ± 2·98 对 20·71 ± 1·08%；P < 0·001）。然而，NDMM 组和 NC 组之间的 CD4 T 细胞和自然杀伤（NK）细胞的 PD-1 表达没有显著差异。此外，共培养试验显示 BMSCs 显著抑制了 CD8 T 细胞的功能。然而，PD-L1 抑制剂可有效逆转 BMSC 对 CD8 T 细胞的抑制作用。我们还发现，PD-L1 抑制剂与泊马度胺的联合使用可进一步增强 CD8 T 细胞对 MM 细胞的杀伤作用。综上所述，我们的研究结果表明，MM 患者的 BMSCs 可能通过 PD-1/PD-L1 轴诱导 CD8 T 细胞凋亡，并抑制 CD8 T 细胞中穿孔素和颗粒酶 B 的释放，从而促进 MM 的免疫逃逸。
