Choi Ji-Na, Sun Eun Gene, Cho Sang-Hee
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
Chonnam Med J. 2019 Jan;55(1):31-39. doi: 10.4068/cmj.2019.55.1.31. Epub 2019 Jan 25.
Myeloid derived suppressor cells (MDSCs) are a heterogenous population of immature cells that play a critical role in tumor associated immune suppression. In tumor conditions, the population of MDSCs increases. The main feature of these cells is their ability to suppress the T cell response in antigen specific or nonspecific manners depending on the condition of T cell activation. IL-12 can modulate MDSC in preliminary reports, so we investigated how IL-12 can affect MDSC in a tumor microenvironment. After implanting tumor based cells on syngeneic host, 4T-1/BALB/c or EL4/C57BL6 mice, MDSCs (Gr1+CD11b+) were isolated from splenocytes. Isolated MDSCs were treated with GM-CSF with or without IL-12 and analyzed based on their phenotypes and functions. Treatment of MDSC with IL-12 increased co-stimulatory molecules of CD80, CD86, OX-40L, enhancing the DC phenotype (CD11c) and maturation markers such as p-NF-κB and p-GSK3β. In addition to a change of surface markers, T-cell suppressive function of MDSC after IL-12 treatment was significantly improved compared with the control MDSC. In addition, PD-L1+F4/80+ macrophages, which show aninhibitory effect in phagocytosis, were decreased after IL-12 treatment. The changes of cell surface expression of CD80, CD86, MHC class II were also shown . Our results showed that the IL-12 can modulate MDSC into APC and recover the macrophage function. These results suggested that IL-12 plays a role in improving the tumor immune microenvironment through MDSC modulation.
髓源性抑制细胞（MDSCs）是一群异质性的未成熟细胞，在肿瘤相关的免疫抑制中起关键作用。在肿瘤状态下，MDSCs的数量会增加。这些细胞的主要特征是能够根据T细胞激活的状态，以抗原特异性或非特异性方式抑制T细胞反应。初步报告显示白细胞介素-12（IL-12）可调节MDSCs，因此我们研究了IL-12在肿瘤微环境中如何影响MDSCs。在同基因宿主4T-1/BALB/c或EL4/C57BL6小鼠中植入肿瘤细胞后，从脾细胞中分离出MDSCs（Gr1+CD11b+）。将分离出的MDSCs用含或不含IL-12的粒细胞-巨噬细胞集落刺激因子（GM-CSF）处理，并根据其表型和功能进行分析。用IL-12处理MDSCs可增加共刺激分子CD80、CD86、OX-40L的表达，增强树突状细胞（DC）表型（CD11c）以及诸如磷酸化核因子κB（p-NF-κB）和磷酸化糖原合成酶激酶3β（p-GSK3β）等成熟标志物。除了表面标志物的变化外，与对照MDSCs相比，经IL-12处理后的MDSCs的T细胞抑制功能显著改善。此外，IL-12处理后，在吞噬作用中显示抑制作用的程序性死亡受体-配体1（PD-L1）+F4/80+巨噬细胞数量减少。CD80、CD86、主要组织相容性复合体II类分子的细胞表面表达也发生了变化。我们的结果表明，IL-12可将MDSCs调节为抗原呈递细胞（APC）并恢复巨噬细胞功能。这些结果提示，IL-12通过调节MDSCs在改善肿瘤免疫微环境中发挥作用。
