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Abstract：
Myeloid-derived suppressor cells (MDSCs), which accumulate in tumor bearers, are known to suppress anti-tumor immunity and thus promote tumor progression. MDSCs are considered a major cause of resistance against immune checkpoint inhibitors in patients with cancer. Therefore, MDSCs are potential targets in cancer immunotherapy. In this study, we modified an in vitro method of MDSC differentiation. Upon stimulating bone marrow (BM) cells with granulocyte-macrophage colony-stimulating factor in vitro, we obtained both lymphocyte antigen 6G positive (Ly-6G+) and negative (Ly-6G-) MDSCs (collectively, hereafter referred to as conventional MDSCs), which were non-immunosuppressive and immunosuppressive, respectively. We then found that MDSCs differentiated from Ly-6G- BM (hereafter called 6G- BM-MDSC) suppressed T-cell proliferation more strongly than conventional MDSCs, whereas the cells differentiated from Ly-6G+ BM (hereafter called 6G+ BM-MDSC) were non-immunosuppressive. In line with this, conventional MDSCs or 6G- BM-MDSC, but not 6G+ BM-MDSC, promoted tumor progression in tumor-bearing mice. Moreover, we identified that activated glutathione metabolism was responsible for the enhanced immunosuppressive ability of 6G- BM-MDSC. Finally, we showed that Ly-6G+ cells in 6G- BM-MDSC, which exhibited weak immunosuppression, expressed higher levels of Cybb mRNA, an immunosuppressive gene of MDSCs, than 6G+ BM-MDSC. Together, these data suggest that the depletion of Ly-6G+ cells from the BM cells leads to differentiation of immunosuppressive Ly-6G+ MDSCs. In summary, we propose a better method for MDSC differentiation in vitro. Moreover, our findings contribute to the understanding of MDSC subpopulations and provide a basis for further research on MDSCs.
摘要：
髓源性抑制细胞（MDSCs），积聚在肿瘤携带者身上，已知抑制抗肿瘤免疫并因此促进肿瘤进展。MDSC被认为是癌症患者对免疫检查点抑制剂产生耐药性的主要原因。因此,MDSCs是癌症免疫治疗的潜在靶标。在这项研究中,我们修改了MDSC分化的体外方法。在体外用粒细胞-巨噬细胞集落刺激因子刺激骨髓（BM）细胞时，我们获得了淋巴细胞抗原6G阳性（Ly-6G）和阴性（Ly-6G-）MDSCs（统称，以下称为常规MDSCs)，非免疫抑制和免疫抑制，分别。然后我们发现从Ly-6G-BM（以下称为6G-BM-MDSC）分化的MDSCs比常规MDSCs更强烈地抑制T细胞增殖。而从Ly-6GBM（以下称为6GBM-MDSC）分化的细胞是非免疫抑制性的。与此相符,常规MDSCs或6G-BM-MDSC，但不是6G+BM-MDSC，促进荷瘤小鼠的肿瘤进展。此外，我们发现活化的谷胱甘肽代谢是6G-BM-MDSC免疫抑制能力增强的原因。最后,我们表明，6G-BM-MDSC中的Ly-6G+细胞，表现出微弱的免疫抑制，表达更高水平的CybbmRNA，MDSCs的免疫抑制基因，比6G+BM-MDSC。一起,这些数据表明,Ly-6G+细胞从BM细胞的消耗导致免疫抑制性Ly-6G+MDSC的分化.总之,我们提出了一种更好的MDSC体外分化方法。此外，我们的研究结果有助于了解MDSC亚群，并为进一步研究MDSCs提供基础。
