The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells
The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells
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DOI：
10.1080/2162402x.2016.1247135
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Liu, Kebin
中科院分区：
文献类型：
--
作者：
Lu, Chunwan;Redd, Priscilla S.;Liu, Kebin
程序性死亡配体1（PD-L1）是一种抑制性配体，与PD-1结合以抑制T细胞活化。 PD-L1在肿瘤细胞中具有组成型表达和诱导，但是髓样衍生的抑制细胞（MDSC）的PD-L1的表达谱和调节机制在很大程度上未知。我们报告说，PD-L1在肿瘤浸润的白细胞中大量表达，而微卫星稳定和微卫星稳定结肠癌的患者均表达PD-L1。人类结肠癌患者外周血的约60％CD11b（+）CD33（+）HLA-DR-MDSC是PD-L1（+）。肿瘤小鼠的PD-L1（+）MDSC也明显高于无肿瘤小鼠。有趣的是，在肿瘤微环境中观察到最高的PD-L1（+）MDSC，其中56-71％的肿瘤浸润MDSC在体内为PD-L1（+）。相比之下，与肿瘤组织相比，继发性淋巴器官和外周血中的PD-L1（+）MDSC明显较小，而骨髓MDSC在肿瘤小鼠中基本上是PD-L1（ - ）。 IFNγ在肿瘤组织的细胞中高度表达，IFNG中和显着降低了体内肿瘤微环境中的PD-L1（+）MDSC。但是，IFNγ激活的PSTAT1不与MDSC中的CD274启动子结合。取而代之的是，PSTAT1在MDSC中激活IRF1，IRF5，IRF7和IRF8的表达，并且仅PSTAT1激活的IRF1在CD274启动子中体外和染色体与唯一的IRF结合序列元件结合，以激活PD-L1转录。我们的数据确定PD-L1在肿瘤浸润的MDSC中高度表达，并且在淋巴器官中的程度较低，而PSTAT1-IRF1轴则调节MDSC中的PD-L1表达。
Programmed death-ligand 1 (PD-L1) is an inhibitory ligand that binds to PD-1 to suppress T cell activation. PD-L1 is constitutively expressed and inducible in tumor cells, but the expression profiles and regulatory mechanism of PD-L1 in myeloid-derived suppressor cells (MDSCs) are largely unknown. We report that PD-L1 is abundantly expressed in tumor-infiltrating leukocytes in human patients with both microsatellite instable and microsatellite stable colon cancer. About 60% CD11b(+)CD33(+)HLA-DR- MDSCs from peripheral blood of human colon cancer patients are PD-L1(+). PD-L1(+) MDSCs are also significantly higher in tumor-bearing mice than in tumor-free mice. Interestingly, the highest PD-L1(+) MDSCs were observed in the tumor microenvironment in which 56-71% tumor-infiltrating MDSCs are PD-L1(+) in vivo. In contrast, PD-L1(+) MDSCs are significantly less in secondary lymphoid organs and peripheral blood as compared to the tumor tissues, whereas bone marrow MDSCs are essentially PD-L1(-) in tumor-bearing mice. IFN gamma is highly expressed in cells of the tumor tissues and IFNg neutralization significantly decreased PD-L1(+) MDSCs in the tumor microenvironment in vivo. However, IFN gamma-activated pSTAT1 does not bind to the cd274 promoter in MDSCs. Instead, pSTAT1 activates expression of IRF1, IRF5, IRF7 and IRF8 in MDSCs, and only pSTAT1-activated IRF1 binds to a unique IRF-binding sequence element in vitro and chromatin in vivo in the cd274 promoter to activate PD-L1 transcription. Our data determine that PD-L1 is highly expressed in tumor-infiltrating MDSCs and in a lesser degree in lymphoid organs, and the pSTAT1-IRF1 axis regulates PD-L1 expression in MDSCs.